Hepatitis B antiviral agents

ABSTRACT

The present invention includes a method of inhibiting, suppressing or preventing HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of at least one compound of the invention.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/723,869, filed Dec. 21, 2012, which claims priority to U.S.Provisional Application Nos. 61/578,716, filed on Dec. 21, 2011 and61/709,331, filed on Oct. 3, 2012. The entire contents of theseapplications are herein incorporated by reference in their entireties.

BACKGROUND OF THE INVENTION

Chronic hepatitis B virus (HBV) infection is a significant global healthproblem, affecting over 5% of the world population (over 350 millionpeople worldwide and 1.25 million individuals in the U.S.).

Despite the availability of a prophylactic HBV vaccine, the burden ofchronic HBV infection continues to be a significant unmet worldwidemedical problem, due to suboptimal treatment options and sustained ratesof new infections in most parts of the developing world. Currenttreatments do not provide a cure and are limited to only two classes ofagents (interferon and nucleoside analogues/inhibitors of the viralpolymerase); drug resistance, low efficacy, and tolerability issueslimit their impact. The low cure rates of HBV are attributed at least inpart to the presence and persistence of covalently closed circular DNA(cccDNA) in the nucleus of infected hepatocytes. However, persistentsuppression of HBV DNA slows liver disease progression and helps toprevent hepatocellular carcinoma. Current therapy goals for HBV-infectedpatients are directed to reducing serum HBV DNA to low or undetectablelevels, and to ultimately reducing or preventing the development ofcirrhosis and hepatocellular carcinoma.

There is a need in the art for novel therapeutic agents that treat,ameliorate or prevent HBV infection. Administration of these therapeuticagents to an HBV infected patient, either as monotherapy or incombination with other HBV treatments or ancillary treatments, will leadto significantly improved prognosis, diminished progression of thedisease, and enhanced seroconversion rates.

SUMMARY OF THE INVENTION

Provided herein are compounds useful for the treatment of HBV infectionin man.

Accordingly, in an aspect, provided herein is a compound of formula (I),or a salt, solvate, or N-oxide thereof:

In an embodiment, compounds of formula (I) are of the formula (II):

or pharmaceutically acceptable salts thereof.

In an embodiment, compounds of the formula (II) are of the formula(IIa), (IIb), and (IIc).

In another embodiment, the compound of formula (I) has the formula(III):

In another aspect, provided herein are compounds having the formula IV:

or pharmaceutically acceptable salts thereof.

In an embodiment, compounds of formula IV are of the formula IVa, IVb,and IVc, or pharmaceutically acceptable salts of those compounds.

In another aspect, provided herein are compounds of formula V:

or pharmaceutically acceptable salts thereof.

In still another aspect, provided herein are compounds of formula VI:

or pharmaceutically acceptable salts thereof.

In an embodiment, compounds of formula VI have the formula VIa or VIb,or pharmaceutically acceptable salts of those compounds,

In another aspect, provided herein are compounds of formula VII:

or pharmaceutically acceptable salts thereof.

Also provided herein are compositions comprising a compound providedherein (also referred to herein as “a compound of the invention”). In anembodiment, the composition is pharmaceutical and further comprises atleast one pharmaceutically acceptable carrier.

In an aspect, provided herein is a method of treating, eradicating,reducing, slowing, or inhibiting an HBV infection in an individual inneed thereof, comprising administering to the individual atherapeutically effective amount of a compound of the invention.

In another aspect, provided herein is a method of reducing the viralload associated with an HBV infection in an individual in need thereof,comprising administering to the individual a therapeutically effectiveamount of a compound of the invention.

In still another aspect, provided herein is a method of reducingreoccurrence of an HBV infection in an individual in need thereof,comprising administering to the individual a therapeutically effectiveamount of a compound of the invention.

In yet another aspect, provided herein is a method of reducing anadverse physiological impact of an HBV infection in an individual inneed thereof, comprising administering to the individual atherapeutically effective amount of a compound of the invention.

Also provided herein are methods of inducing remission of hepatic injuryfrom an HBV infection in an individual in need thereof, comprisingadministering to the individual a therapeutically effective amount of acompound of the invention.

In another aspect, provided herein is a method of reducing thephysiological impact of long-term antiviral therapy for HBV infection inan individual in need thereof, comprising administering to theindividual a therapeutically effective amount of a compound of theinvention.

Also provided herein is a a method of prophylactically treating an HBVinfection in an individual in need thereof, wherein the individual isafflicted with a latent HBV infection, comprising administering to theindividual a therapeutically effective amount of a compound of theinvention.

In any above methods, the compound can be administered in combinationwith an additional therapeutic agent. In an embodiment, the additionaltherapeutic agent selected from the group consisting of a HBV polymeraseinhibitor, interferon, viral entry inhibitor, viral maturationinhibitor, literature-described capsid assembly modulator, reversetranscriptase inhibitor, a TLR-agonist, and agents of distinct orunknown mechanism, and a combination thereof.

In another embodiment, the additional therapeutic agent selected fromimmune modulator or immune stimulator therapies, which includesbiological agents belonging to the interferon class, such as interferonalpha 2a or 2b or modified interferons such as pegylated interferon,alpha 2a, alpha 2b, lamda; or TLR modulators such as TLR-7 agonists orTLR-9 agonists, or antiviral agents that block viral entry or maturationor target the HBV polymerase such as nucleoside or nucleotide ornon-nucleos(t)ide polymerase inhibitors, and agents of distinct orunknown mechanism including agents that disrupt the function of otheressential viral protein(s) or host proteins required for HBV replicationor persistence.

In an embodiment of the combination therapy, the reverse transcriptaseinhibitor is at least one of Zidovudine, Didanosine, Zalcitabine, ddA,Stavudine, Lamivudine, Abacavir, Emtricitabine, Entecavir, Apricitabine,Atevirapine, ribavirin, acyclovir, famciclovir, valacyclovir,ganciclovir, valganciclovir, Tenofovir, Adefovir, PMPA, cidofovir,Efavirenz, Nevirapine, Delavirdine, or Etravirine.

In another embodiment of the combination therapy, the TLR-7 agonist isselected from the group consisting of SM360320(9-benzyl-8-hydroxy-2-(2-methoxy-ethoxy)adenine) and AZD 8848(methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(4-morpholinyl)propyl]amino}methyl)phenyl]acetate).

In an embodiment of these combination therapies, the compound and theadditional therapeutic agent are co-formulated. In another embodiment,the compound and the additional therapeutic agent are co-administered.

In another embodiment of the combination therapy, administering thecompound of the invention allows for administering of the additionaltherapeutic agent at a lower dose or frequency as compared to theadministering of the at least one additional therapeutic agent alonethat is required to achieve similar results in prophylactically treatingan HBV infection in an individual in need thereof.

In another embodiment of the combination therapy, before administeringthe therapeutically effective amount of the compound of the invention,the individual is known to be refractory to a compound selected from thegroup consisting of a HBV polymerase inhibitor, interferon, viral entryinhibitor, viral maturation inhibitor, distinct capsid assemblymodulator, antiviral compounds of distinct or unknown mechanism, andcombination thereof.

In still another embodiment of the method, administering the compound ofthe invention reduces viral load in the individual to a greater extentcompared to the administering of a compound selected from the groupconsisting of a HBV polymerase inhibitor, interferon, viral entryinhibitor, viral maturation inhibitor, distinct capsid assemblymodulator, antiviral compounds of distinct or unknown mechanism, andcombination thereof.

In another embodiment, administering of the compound of the inventioncauses a lower incidence of viral mutation and/or viral resistance thanthe administering of a compound selected from the group consisting of aHBV polymerase inhibitor, interferon, viral entry inhibitor, viralmaturation inhibitor, distinct capsid assembly modulator, antiviralcompounds of distinct or unknown mechanism, and combination thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

For the purpose of illustrating the invention, there are depicted in thedrawings certain embodiments of the invention. However, the invention isnot limited to the precise arrangements and instrumentalities of theembodiments depicted in the drawings.

FIG. 1 is a scheme illustrating the fluorescence quenching in vitro HBVassembly assay. This assay utilizes a mutant C150 HBV capsid proteinwherein all wild-type cysteines are mutated to alanines, but aC-terminal cysteine residue is preserved and is labeled with fluorescentBoDIPY-FL dye. The fluorescence signal of HBV C150Bo protein decreasesduring the capsid assembly process, and thus monitoring the fluorescenceof the reaction provides a good readout on the extent of the capsidassembly.

DETAILED DESCRIPTION OF THE INVENTION

Provided herein are compounds that are useful in the treatment andprevention of HBV in man. In a non-limiting aspect, these compoundsmodulate and/or disrupt HBV assembly by interacting with HBV capsid toafford defective viral particles with greatly reduced virulence. Thecompounds of the invention have potent antiviral activity, exhibitfavorable metabolic, tissue distribution, safety and pharmaceuticalprofiles, and are suitable for use in man.

The HBV capsid protein plays essential functions during the viral lifecycle. HBV capsid/core proteins form metastable viral particles orprotein shells that protect the viral genome during intercellularpassage, and also play a central role in viral replication processes,including genome encapsidation, genome replication, and virionmorphogenesis and egress. Capsid structures also respond toenvironmental cues to allow un-coating after viral entry. Consistently,proper capsid assembly has been found to be critical for viralinfectivity.

The crucial function of HBV capsid proteins imposes stringentevolutionary constraints on the viral capsid protein sequence, leadingto the observed low sequence variability and high conservation.Consistently, mutations in HBV capsid that disrupt its assembly arelethal, and mutations that perturb capsid stability severely attenuateviral replication. The more conserved a drug target is, the fewerreplication-competent resistance mutations are acquired by patients.Indeed, natural mutations in HBV capsid for chronically infectedpatients accumulate in only four out of 183 residues in the full lengthprotein. Thus, HBV capsid assembly inhibitors may elicit lower drugresistance emergence rates relative to existing HBV antivirals. Further,drug therapy that targets HBV capsid could be less prone todrug-resistant mutations when compared to drugs that target traditionalNA enzyme active sites. Reports describing compounds that bind viralcapsids and inhibit replication of HIV, rhinovirus and HBV providestrong pharmacological proof of concept for viral capsid proteins asantiviral drug targets.

In one aspect, the compounds of the invention are useful in HBVtreatment by disrupting, accelerating, reducing, delaying and/orinhibiting normal viral capsid assembly and/or disassembly of immatureor mature particles, thereby inducing aberrant capsid morphology andleading to antiviral effects such as disruption of virion assemblyand/or disassembly, virion maturation, and/or virus egress. In oneembodiment, a disruptor of capsid assembly interacts with mature orimmature viral capsid to perturb the stability of the capsid, thusaffecting assembly and/or disassembly. In another embodiment, adisruptor of capsid assembly perturbs protein folding and/or saltbridges required for stability, function and/or normal morphology of theviral capsid, thereby disrupting and/or accelerating capsid assemblyand/or disassembly. In yet another embodiment, the compounds of theinvention bind capsid and alter metabolism of cellular polyproteins andprecursors, leading to abnormal accumulation of protein monomers and/oroligomers and/or abnormal particles, which causes cellular toxicity anddeath of infected cells. In another embodiment, the compounds of theinvention cause failure of the formation of capsid of optimal stability,affecting efficient uncoating and/or disassembly of viruses (e.g.,during infectivity).

In one embodiment, the compounds of the invention disrupt and/oraccelerate capsid assembly and/or disassembly when the capsid protein isimmature. In another embodiment, the compounds of the invention disruptand/or accelerate capsid assembly and/or disassembly when the capsidprotein is mature. In yet another embodiment, the compounds of theinvention disrupt and/or accelerate capsid assembly and/or disassemblyduring vial infectivity. In yet another embodiment, the disruptionand/or acceleration of capsid assembly and/or disassembly attenuates HBVviral infectivity and/or reduces viral load. In yet another embodiment,disruption, acceleration, inhibition, delay and/or reduction of capsidassembly and/or disassembly eradicates the virus from the host organism.In yet another embodiment, eradication of the HBV from a hostadvantageously obviates the need for chronic long-term therapy and/orreduces the duration of long-term therapy.

In one embodiment, the compounds described herein are suitable formonotherapy and are effective against natural or native HBV strains andagainst HBV strains resistant to currently known drugs. In anotherembodiment, the compounds described herein are suitable for use incombination therapy.

In another embodiment, the compounds of the invention can be used inmethods of modulating (e.g., inhibit, disrupt or accelerate) theactivity of HBV cccDNA. In yet another embodiment, the compounds of theinvention can be used in methods of diminishing or preventing theformation of HBV cccDNA.

DEFINITIONS

As used herein, each of the following terms has the meaning associatedwith it in this section.

Unless defined otherwise, all technical and scientific terms used hereingenerally have the same meaning as commonly understood by one ofordinary skill in the art to which this invention belongs. Generally,the nomenclature used herein and the laboratory procedures in cellculture, molecular genetics, organic chemistry, and peptide chemistryare those well-known and commonly employed in the art.

As used herein, the articles “a” and “an” refer to one or to more thanone (i.e. to at least one) of the grammatical object of the article. Byway of example, “an element” means one element or more than one element.Furthermore, use of the term “including” as well as other forms, such as“include”, “includes,” and “included,” is not limiting.

As used herein, the term “about” will be understood by persons ofordinary skill in the art and will vary to some extent on the context inwhich it is used. As used herein when referring to a measurable valuesuch as an amount, a temporal duration, and the like, the term “about”is meant to encompass variations of ±20% or ±10%, more preferably ±5%,even more preferably ±1%, and still more preferably ±0.1% from thespecified value, as such variations are appropriate to perform thedisclosed methods.

As used herein, the term “capsid assembly modulator” refers to acompound that disrupts and/or accelerates and/or inhibits and/or hindersand/or delays and or reduces and/or modifies normal capsid assembly(e.g., during maturation) and/or normal capsid disassembly (e.g., duringinfectivity) and/or perturbs capsid stability, thereby inducing aberrantcapsid morphology and function. In one embodiment, a capsid assemblymodulator accelerates capsid assembly and/or disassembly, therebyinducing aberrant capsid morphology. In another embodiment, a capsidassembly modulator interacts (e.g. binds at an active site, binds at anallosteric site, modifies and/or hinders folding and the like) with themajor capsid assembly protein (CA), thereby disrupting capsid assemblyand/or disassembly. In yet another embodiment, a capsid assemblymodulator causes a perturbation in structure and/or function of CA(e.g., ability of CA to assemble, disassemble, bind to a substrate, foldinto a suitable conformation, or the like), which attenuates viralinfectivity and/or is lethal to the virus.

As used herein, the term “literature-described capsid assemblymodulator” refers a capsid assembly modulator that is not a compound ofthe present invention.

As used herein, the term “treatment” or “treating,” is defined as theapplication or administration of a therapeutic agent, i.e., a compoundof the invention (alone or in combination with another pharmaceuticalagent), to a patient, or application or administration of a therapeuticagent to an isolated tissue or cell line from a patient (e.g., fordiagnosis or ex vivo applications), who has HBV infection, a symptom ofHBV infection or the potential to develop HBV infection, with thepurpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate,improve or affect HBV infection, the symptoms of HBV infection or thepotential to develop HBV infection. Such treatments may be specificallytailored or modified, based on knowledge obtained from the field ofpharmacogenomics.

As used herein, the term “prevent” or “prevention” means no disorder ordisease development if none had occurred, or no further disorder ordisease development if there had already been development of thedisorder or disease. Also considered is the ability of one to preventsome or all of the symptoms associated with the disorder or disease.

As used herein, the term “patient,” “individual” or “subject” refers toa human or a non-human mammal Non-human mammals include, for example,livestock and pets, such as ovine, bovine, porcine, canine, feline andmurine mammals. Preferably, the patient, subject or individual is human.

As used herein, the terms “effective amount,” “pharmaceuticallyeffective amount” and “therapeutically effective amount” refer to anontoxic but sufficient amount of an agent to provide the desiredbiological result. That result may be reduction and/or alleviation ofthe signs, symptoms, or causes of a disease, or any other desiredalteration of a biological system. An appropriate therapeutic amount inany individual case may be determined by one of ordinary skill in theart using routine experimentation.

As used herein, the term “pharmaceutically acceptable” refers to amaterial, such as a carrier or diluent, which does not abrogate thebiological activity or properties of the compound, and is relativelynon-toxic, i.e., the material may be administered to an individualwithout causing undesirable biological effects or interacting in adeleterious manner with any of the components of the composition inwhich it is contained.

As used herein, the language “pharmaceutically acceptable salt” refersto a salt of the administered compounds prepared from pharmaceuticallyacceptable non-toxic acids, including inorganic acids, organic acids,solvates, hydrates, or clathrates thereof. Examples of such inorganicacids are hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric,phosphoric, acetic, hexafluorophosphoric, citric, gluconic, benzoic,propionic, butyric, sulfosalicylic, maleic, lauric, malic, fumaric,succinic, tartaric, amsonic, pamoic, p-tolunenesulfonic, and mesylic.Appropriate organic acids may be selected, for example, from aliphatic,aromatic, carboxylic and sulfonic classes of organic acids, examples ofwhich are formic, acetic, propionic, succinic, camphorsulfonic, citric,fumaric, gluconic, isethionic, lactic, malic, mucic, tartaric,para-toluenesulfonic, glycolic, glucuronic, maleic, furoic, glutamic,benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic(pamoic), methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic(besylate), stearic, sulfanilic, alginic, galacturonic, and the like.Furthermore, pharmaceutically acceptable salts include, by way ofnon-limiting example, alkaline earth metal salts (e.g., calcium ormagnesium), alkali metal salts (e.g., sodium-dependent or potassium),and ammonium salts.

As used herein, the term “pharmaceutically acceptable carrier” means apharmaceutically acceptable material, composition or carrier, such as aliquid or solid filler, stabilizer, dispersing agent, suspending agent,diluent, excipient, thickening agent, solvent or encapsulating material,involved in carrying or transporting a compound useful within theinvention within or to the patient such that it may perform its intendedfunction. Typically, such constructs are carried or transported from oneorgan, or portion of the body, to another organ, or portion of the body.Each carrier must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation, including the compound usefulwithin the invention, and not injurious to the patient. Some examples ofmaterials that may serve as pharmaceutically acceptable carriersinclude: sugars, such as lactose, glucose and sucrose; starches, such ascorn starch and potato starch; cellulose, and its derivatives, such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients, such as cocoabutter and suppository waxes; oils, such as peanut oil, cottonseed oil,safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols,such as propylene glycol; polyols, such as glycerin, sorbitol, mannitoland polyethylene glycol; esters, such as ethyl oleate and ethyl laurate;agar; buffering agents, such as magnesium hydroxide and aluminumhydroxide; surface active agents; alginic acid; pyrogen-free water;isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffersolutions; and other non-toxic compatible substances employed inpharmaceutical formulations. As used herein, “pharmaceuticallyacceptable carrier” also includes any and all coatings, antibacterialand antifungal agents, and absorption delaying agents, and the like thatare compatible with the activity of the compound useful within theinvention, and are physiologically acceptable to the patient.Supplementary active compounds may also be incorporated into thecompositions. The “pharmaceutically acceptable carrier” may furtherinclude a pharmaceutically acceptable salt of the compound useful withinthe invention. Other additional ingredients that may be included in thepharmaceutical compositions used in the practice of the invention areknown in the art and described, for example in Remington'sPharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton,Pa.), which is incorporated herein by reference.

As used herein, the term “composition” or “pharmaceutical composition”refers to a mixture of at least one compound useful within the inventionwith a pharmaceutically acceptable carrier. The pharmaceuticalcomposition facilitates administration of the compound to a patient orsubject. Multiple techniques of administering a compound exist in theart including, but not limited to, intravenous, oral, aerosol,parenteral, ophthalmic, pulmonary and topical administration.

As used herein, the term “alkyl,” by itself or as part of anothersubstituent means, unless otherwise stated, a straight or branched chainhydrocarbon having the number of carbon atoms designated (i.e., C₁₋₆means one to six carbon atoms) and includes straight, branched chain, orcyclic substituent groups. Examples include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, andcyclopropylmethyl. Most preferred is (C₁-C₆)alkyl, particularly ethyl,methyl, isopropyl, isobutyl, n-pentyl, n-hexyl and cyclopropylmethyl.

As used herein, the term “substituted alkyl” means alkyl as definedabove, substituted by one, two or three substituents selected from thegroup consisting of halogen, —OH, alkoxy, —NH₂, —N(CH₃)₂, —C(C═O)OH,trifluoromethyl, —C≡N, —C(═O)O(C₁-C₄)alkyl, —C(C═O)NH₂, —SO₂NH₂,—C(═NH)NH₂, and —NO₂, preferably containing one or two substituentsselected from halogen, —OH, alkoxy, —NH₂, trifluoromethyl, —N(CH₃)₂, and—C(C═O)OH, more preferably selected from halogen, alkoxy and —OH.Examples of substituted alkyls include, but are not limited to,2,2-difluoropropyl, 2-carboxycyclopentyl and 3-chloropropyl.

As used herein, the term “heteroalkyl” by itself or in combination withanother term means, unless otherwise stated, a stable straight orbranched chain alkyl group consisting of the stated number of carbonatoms and one or two heteroatoms selected from the group consisting ofO, N, and S, and wherein the nitrogen and sulfur atoms may be optionallyoxidized and the nitrogen heteroatom may be optionally quaternized. Theheteroatom(s) may be placed at any position of the heteroalkyl group,including between the rest of the heteroalkyl group and the fragment towhich it is attached, as well as attached to the most distal carbon atomin the heteroalkyl group. Examples include: —O—CH₂—CH₂—CH₃,—CH₂—CH₂—CH₂—OH, —CH₂—CH₂—NH—CH₃, —CH₂—S—CH₂—CH₃, and —CH₂CH₂—S(═O)—CH₃.Up to two heteroatoms may be consecutive, such as, for example,—CH₂—NH—OCH₃, or —CH₂—CH₂—S—S—CH₃. Preferred heteroalkyl groups have1-10 carbons.

As used herein, the term “alkoxy” employed alone or in combination withother terms means, unless otherwise stated, an alkyl group having thedesignated number of carbon atoms, as defined above, connected to therest of the molecule via an oxygen atom, such as, for example, methoxy,ethoxy, 1-propoxy, 2-propoxy(isopropoxy) and the higher homologs andisomers. Preferred are (C₁-C₃)alkoxy, particularly ethoxy and methoxy.

As used herein, the term “halo” or “halogen” alone or as part of anothersubstituent means, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom, preferably, fluorine, chlorine, or bromine,more preferably, fluorine or chlorine.

As used herein, the term “cycloalkyl” refers to a mono cyclic orpolycyclic non-aromatic radical, wherein each of the atoms forming thering (i.e., skeletal atoms) is a carbon atom. In one embodiment, thecycloalkyl group is saturated or partially unsaturated. In anotherembodiment, the cycloalkyl group is fused with an aromatic ring.Cycloalkyl groups include groups having from 3 to 10 ring atoms.Illustrative examples of cycloalkyl groups include, but are not limitedto, the following moieties:

Monocyclic cycloalkyls include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.Dicyclic cycloalkyls include, but are not limited to,tetrahydronaphthyl, indanyl, and tetrahydropentalene. Polycycliccycloalkyls include adamantine and norbornane. The term cycloalkylincludes “unsaturated nonaromatic carbocyclyl” or “nonaromaticunsaturated carbocyclyl” groups, both of which refer to a nonaromaticcarbocycle as defined herein, which contains at least one carbon carbondouble bond or one carbon carbon triple bond.

As used herein, the term “heterocycloalkyl” or “heterocyclyl” refers toa heteroalicyclic group containing one to four ring heteroatoms eachselected from O, S and N. In one embodiment, each heterocycloalkyl grouphas from 4 to 10 atoms in its ring system, with the proviso that thering of said group does not contain two adjacent O or S atoms. Inanother embodiment, the heterocycloalkyl group is fused with an aromaticring. In one embodiment, the nitrogen and sulfur heteroatoms may beoptionally oxidized, and the nitrogen atom may be optionallyquaternized. The heterocyclic system may be attached, unless otherwisestated, at any heteroatom or carbon atom that affords a stablestructure. A heterocycle may be aromatic or non-aromatic in nature. Inone embodiment, the heterocycle is a heteroaryl.

An example of a 3-membered heterocycloalkyl group includes, and is notlimited to, aziridine. Examples of 4-membered heterocycloalkyl groupsinclude, and are not limited to, azetidine and a beta lactam. Examplesof 5-membered heterocycloalkyl groups include, and are not limited to,pyrrolidine, oxazolidine and thiazolidinedione. Examples of 6-memberedheterocycloalkyl groups include, and are not limited to, piperidine,morpholine and piperazine. Other non-limiting examples ofheterocycloalkyl groups are:

Examples of non-aromatic heterocycles include monocyclic groups such asaziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine,pyrroline, pyrazolidine, imidazoline, dioxolane, sulfolane,2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane,piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine,morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran,1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine, 1,3-dioxepane,4,7-dihydro-1,3-dioxepin, and hexamethyleneoxide.

As used herein, the term “aromatic” refers to a carbocycle orheterocycle with one or more polyunsaturated rings and having aromaticcharacter, i.e., having (4n+2) delocalized π (pi) electrons, where n isan integer.

As used herein, the term “aryl,” employed alone or in combination withother terms, means, unless otherwise stated, a carbocyclic aromaticsystem containing one or more rings (typically one, two or three rings),wherein such rings may be attached together in a pendent manner, such asa biphenyl, or may be fused, such as naphthalene. Examples of arylgroups include phenyl, anthracyl, and naphthyl. Preferred examples arephenyl and naphthyl, most preferred is phenyl.

As used herein, the term “aryl-(C₁-C₃)alkyl” means a functional groupwherein a one- to three-carbon alkylene chain is attached to an arylgroup, e.g., —CH₂CH₂-phenyl. Preferred is aryl-CH₂— and aryl-CH(CH₃)—.The term “substituted aryl-(C₁-C₃)alkyl” means an aryl-(C₁-C₃)alkylfunctional group in which the aryl group is substituted. Preferred issubstituted aryl(CH₂)—. Similarly, the term “heteroaryl-(C₁-C₃)alkyl”means a functional group wherein a one to three carbon alkylene chain isattached to a heteroaryl group, e.g., —CH₂CH₂-pyridyl. Preferred isheteroaryl-(CH₂)—. The term “substituted heteroaryl-(C₁-C₃)alkyl” meansa heteroaryl-(C₁-C₃)alkyl functional group in which the heteroaryl groupis substituted. Preferred is substituted heteroaryl-(CH₂)—.

As used herein, the term “heteroaryl” or “heteroaromatic” refers to aheterocycle having aromatic character. A polycyclic heteroaryl mayinclude one or more rings that are partially saturated. Examples includethe following moieties:

Examples of heteroaryl groups also include pyridyl, pyrazinyl,pyrimidinyl (particularly 2- and 4-pyrimidinyl), pyridazinyl, thienyl,furyl, pyrrolyl (particularly 2-pyrrolyl), imidazolyl, thiazolyl,oxazolyl, pyrazolyl (particularly 3- and 5-pyrazolyl), isothiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl,1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and1,3,4-oxadiazolyl.

Examples of polycyclic heterocycles and heteroaryls include indolyl(particularly 3-, 4-, 5-, 6- and 7-indolyl), indolinyl, quinolyl,tetrahydroquinolyl, isoquinolyl (particularly 1- and 5-isoquinolyl),1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl (particularly 2-and 5-quinoxalinyl), quinazolinyl, phthalazinyl, 1,8-naphthyridinyl,1,4-benzodioxanyl, coumarin, dihydrocoumarin, 1,5-naphthyridinyl,benzofuryl (particularly 3-, 4-, 5-, 6- and 7-benzofuryl),2,3-dihydrobenzofuryl, 1,2-benzisoxazolyl, benzothienyl (particularly3-, 4-, 5-, 6-, and 7-benzothienyl), benzoxazolyl, benzothiazolyl(particularly 2-benzothiazolyl and 5-benzothiazolyl), purinyl,benzimidazolyl (particularly 2-benzimidazolyl), benzotriazolyl,thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrrolizidinyl, andquinolizidinyl.

As used herein, the term “substituted” means that an atom or group ofatoms has replaced hydrogen as the substituent attached to anothergroup. The term “substituted” further refers to any level ofsubstitution, namely mono-, di-, tri-, tetra-, or penta-substitution,where such substitution is permitted. The substituents are independentlyselected, and substitution may be at any chemically accessible position.In one embodiment, the substituents vary in number between one and four.In another embodiment, the substituents vary in number between one andthree. In yet another embodiment, the substituents vary in numberbetween one and two.

As used herein, the term “optionally substituted” means that thereferenced group may be substituted or unsubstituted. In one embodiment,the referenced group is optionally substituted with zero substituents,i.e., the referenced group is unsubstituted. In another embodiment, thereferenced group is optionally substituted with one or more additionalgroup(s) individually and independently selected from groups describedherein.

In one embodiment, the substituents are independently selected from thegroup consisting of oxo, halogen, —CN, —NH₂, —OH, —NH(CH₃), —N(CH₃)₂,alkyl (including straight chain, branched and/or unsaturated alkyl),substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, fluoro alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted alkoxy, fluoroalkoxy,—S-alkyl, S(═O)₂alkyl, —C(═O)NH[substituted or unsubstituted alkyl, orsubstituted or unsubstituted phenyl], —C(═O)N[H or alkyl]₂,—OC(═O)N[substituted or unsubstituted alkyl]₂, —NHC(═O)NH[substituted orunsubstituted alkyl, or substituted or unsubstituted phenyl],—NHC(═O)alkyl, —N[substituted or unsubstituted alkyl]C(═O)[substitutedor unsubstituted alkyl], —NHC(═O)[substituted or unsubstituted alkyl],—C(OH)[substituted or unsubstituted alkyl]₂, and —C(NH₂)[substituted orunsubstituted alkyl]₂. In another embodiment, by way of example, anoptional substituent is selected from oxo, fluorine, chlorine, bromine,iodine, —CN, —NH₂, —OH, —NH(CH₃), —N(CH₃)₂, —CH₃, —CH₂CH₃, —CH(CH₃)₂,—CF₃, —CH₂CF₃, —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂, —OCF₃, —OCH₂CF₃,—S(═O)₂—CH₃, —C(C═O)NH₂, —C(C═O)—NHCH₃, —NHC(═O)NHCH₃, —C(C═O)CH₃, and—C(C═O)OH. In yet one embodiment, the substituents are independentlyselected from the group consisting of C₁₋₆ alkyl, —OH, C₁₋₆ alkoxy,halo, amino, acetamido, oxo and nitro. In yet another embodiment, thesubstituents are independently selected from the group consisting ofC₁₋₆ alkyl, C₁₋₆ alkoxy, halo, acetamido, and nitro. As used herein,where a substituent is an alkyl or alkoxy group, the carbon chain may bebranched, straight or cyclic, with straight being preferred.

Compounds of the Invention

The present invention relates to the discovery of compounds that areuseful in the treatment and prevention of HBV in man. In one aspect, thecompounds of the invention are useful in HBV treatment by disrupting,accelerating, reducing delaying and/or inhibiting normal viral capsidassembly and/or disassembly of immature or mature particles, therebyinducing aberrant capsid morphology and leading to antiviral effectssuch as disruption of virion assembly and/or disassembly and/or virionmaturation, and/or virus egress.

The capsid assembly disruptors disclosed herein may be used asmonotherapy and/or in novel cross-class combination regimens fortreating HBV infection in man. Combination therapy with drugs exhibitingdifferent mechanism of action (MOA) that act at different steps in thevirus life cycle may deliver greater efficacy due to additive orsynergistic antiviral effects. Clinically evaluated HIV treatmentregimens have shown that combination therapy improves the efficacy ofviral load reduction, and dramatically reduces emergence of antiviralresistance. Combination therapy for the treatment of Hepatitis C (HCV)virus infection has also resulted in significant improvement insustained antiviral response and eradication rates. Thus, use of the HBVcapsid assembly inhibitors of the present invention in combination with,for example, NA drugs, is likely to deliver a more profound antiviraleffect and greater disease eradication rates than current standards ofcare.

Capsid assembly plays a central role in HBV genome replication. HBVpolymerase binds pre-genomic HBV RNA (pgRNA), and pgRNA encapsidationmust occur prior to HBV DNA synthesis. Moreover, it is well establishedthat nuclear accumulation of the cccDNA replication intermediate, whichis responsible for maintenance of chronic HBV replication in thepresence of nucleoside suppressive therapy, requires the capsid forshuttling HBV DNA to the nuclei. Therefore, the HBV capsid assemblydisruptors of the invention have the potential to increase HBVeradication rates through synergistic or additive suppression of viralgenome replication and to further reduce accumulation of cccDNA whenused alone or in combination with existing nucleoside drugs. The capsidassembly disruptors of the present invention may also alter normal coreprotein degradation, potentially leading to altered MHC-1 antigenpresentation, which may in turn increase seroconversion/eradicationrates through immuno-stimulatory activity, more effectively clearinginfected cells.

In one aspect, drug resistance poses a major threat to current therapiesfor chronic HBV infection, and cross-class combination therapy is aproven strategy for delaying emergence of drug resistance strains. Thecapsid assembly disruptors of the present invention can, whenadministered alone or in combination with other HBV therapy, offerenhanced drug resistant profiles and improved management of chronic HBV.

The compounds useful within the invention may be synthesized usingtechniques well-known in the art of organic synthesis. The startingmaterials and intermediates required for the synthesis may be obtainedfrom commercial sources or synthesized according to methods known tothose skilled in the art.

In one aspect, the compound of the invention is a compound of formula(I), or a salt, solvate, or N-oxide thereof:

wherein:

ring A is a monocyclic or bicyclic aryl or a monocyclic or bicyclicheteroaryl ring;

ring B is a monocyclic or bicyclic aryl or a monocyclic or bicyclicheteroaryl ring;

R¹ is SO₂N(R⁶)R⁷ or C(═O)N(H)R⁶;

R² and R⁵ are independently selected at each occurrence from the groupconsisting of halo, —CN, —NO₂, -(L)_(m)-OR⁸, -(L)_(m)-SR⁹,-(L)_(m)-S(═O)R⁹, -(L)_(m)-S(═O)₂R⁹, -(L)_(m)-NHS(═O)₂R⁹,-(L)_(m)-(═O)R⁹, -(L)_(m)-OC(═O)R⁹, -(L)_(m)CO₂R⁸, -(L)_(m)-OCO₂R⁸,-(L)_(m)-CH(R⁸)₂, -(L)_(m)-N(R⁸)₂, -(L)_(m)-C(═O)N(R⁸)₂,-(L)_(m)-OC(═O)N(R⁸)₂, -(L)_(m)-NHC(═O)NH(R⁸), -(L)_(m)-NHC(═O)R⁹,-(L)_(m)-NHC(═O)OR⁹, -(L)_(m)-COMR⁸)₂, -(L)_(m)C(NH₂)(R⁸)₂, —C₁-C₆alkyl, —C₁-C₆ fluoroalkyl and —C₁-C₆ heteroalkyl;

R³ is C or S(═O);

R⁴ is H, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, —C₁-C₃alkyl-(C₃-C₆ cycloalkyl)or -(L)_(m)-aryl, and wherein the alkyl, heteroalkyl, cycloalkyl or arylgroup is optionally substituted with 0-5 substituents selected from R²;

R⁶ and R⁷ are independently selected from the group consisting of H,C₁-C₆ alkyl, C₁-C₆ fluoroalkyl, C₁-C₆ heteroalkyl, C₃-C₁₀ cycloalkyl,C₂-C₁₀ heterocycloalkyl, aryl, heteroaryl, —C₁-C₄ alkyl-(C₃-C₁₀cycloalkyl), —C₁-C₄ alkyl-(C₂-C₁₀ heterocycloalkyl), —C₁-C₄alkyl-(aryl), or —C₁-C₄ alkyl(heteroaryl), and wherein the alkyl,heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group isoptionally substituted with 0-5 substituents selected from R², or the R⁶and R⁷ groups attached to the same N atom are taken together with the Natom to which they are attached to form an optionally substituted C₂-C₁₀heterocycloalkyl ring, wherein the ring optionally comprises a moietyselected from O, C═O, S(O)_(m), NR⁴S(O)_(m), NR⁴(C═O) or N—R⁴, andwherein the cycloalkyl or heterocycloalkyl ring is optionallysubstituted with 0-5 substituents selected from R²;

each R⁸ is independently, at each occurrence, H, C₁-C₆ alkyl, C₁-C₆fluoroalkyl, C₁-C₆ heteroalkyl, C₃-C₁₀ cycloalkyl, C₂-C₁₀heterocycloalkyl, aryl, heteroaryl, —C₁-C₄ alkyl-(C₃-C₁₀ cycloalkyl),—C₁-C₄ alkyl-(C₂-C₁₀ heterocycloalkyl), —C₁-C₄ alkyl-(aryl), or —C₁-C₄alkyl(heteroaryl), and wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl and heteroaryl is optionally substituted with 0-5substituents selected from R²; or two R⁸ groups attached to the same Nor C atom are taken together with the N or C atom to which they areattached to form an optionally substituted C₂-C₁₀ heterocycloalkyl orC₃-C₁₀ heterocycloalkyl, wherein the ring optionally comprises a moietyselected from O, C═O, S(O)_(m), NR⁴S(O)_(m), NR⁴(C═O) or N—R⁴, andwherein the ring is optionally substituted with 0-5 substituentsselected from R²;

R⁹ is C₁-C₆ alkyl, C₁-C₆ fluoroalkyl, C₁-C₆ heteroalkyl, C₃-C₁₀cycloalkyl, a C₂-C₁₀ heterocycloalkyl, aryl, heteroaryl, —C₁-C₄alkyl-(C₃-C₁₀ cycloalkyl), —C₁-C₄ alkyl-(C₂-C₁₀ heterocycloalkyl),—C₁-C₄ alkyl-(aryl), or —C₁-C₄ alkyl-(heteroaryl), and wherein thealkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroarylring is optionally substituted with 0-5 substituents selected from R²;

each occurrence of x and y is independently selected from the groupconsisting of 0, 1, 2, 3 and 4;

L is independently, at each occurrence, a bivalent radical selected from—(C₁-C₃ alkylene)_(m)-, —(C₃-C₇ cycloalkylene), —(C₁-C₃alkylene)_(m)-O—(C₁-C₃ alkylene)_(m)-, or —(C₁-C₃alkylene)_(m)-NH—(C₁-C₃ alkylene)_(m)-; and,

each occurrence of m is independently 0, 1 or 2.

In one embodiment, ring A is a monocyclic aryl ring optionallysubstituted with 0-3 substituents selected from R². In anotherembodiment, ring A is a monocyclic heteroaryl ring optionallysubstituted with 0-3 substituents selected from R². In yet anotherembodiment, ring A is a bicyclic aryl ring optionally substituted with0-3 substituents selected from R². In yet another embodiment, ring A isa bicyclic heteroaryl ring optionally substituted with 0-3 substituentsselected from R². In yet another embodiment, ring A is optionallysubstituted with zero substituents selected from R².

In one embodiment, ring B is a monocyclic aryl ring optionallysubstituted with 0-3 substituents selected from R⁵. In anotherembodiment, ring B is a monocyclic heteroaryl ring optionallysubstituted with 0-3 substituents selected from R⁵. In yet anotherembodiment, ring B is a bicyclic aryl ring optionally substituted with0-3 substituents selected from R⁵. In yet another embodiment, ring B isa bicyclic heteroaryl ring optionally substituted with 0-3 substituentsselected from R⁵. In yet another embodiment, ring B is optionallysubstituted with zero substituents selected from R⁵.

In one embodiment, B is phenyl; A is aryl or heteroaryl; R¹ isSO₂N(R⁶)R⁷ or C(═O)N(H)R⁶.

In one embodiment, A is phenyl; B is phenyl; R³ is C; R¹ is SO₂N(R⁶)R⁷or C(═O)N(H)R⁶.

In one embodiment, A is phenyl; B is phenyl; x is zero; R³ is C; R¹ isSO₂N(R⁶)R⁷ or C(═O)N(H)R⁶; wherein substituents R¹ and R³ are in a1,3-position (or meta-substitution) with respect to each other.

In one embodiment, A is phenyl; B is phenyl; x is zero; R³ is C; R¹ isSO₂N(R⁶)R⁷; wherein substituents R¹ and R³ are in a 1,3-position (ormeta-substitution) with respect to each other.

In one embodiment, A is phenyl; B is phenyl; x is zero; R³ is C; R¹ isC(═O)N(H)R⁶; wherein substituents R¹ and R³ are in a 1,3-position (ormeta-substitution) with respect to each other.

In one embodiment, x is zero. In another embodiment, x is 1 and R² ishalo.

In one embodiment, the compound of the invention is a compound offormula (II), or a salt, solvate, or N-oxide thereof:

wherein ring B, R⁵, y, R⁴, R², x, and R⁶ have the definitions providedabove for Formula I.

In an embodiment, the compound of formula (II) is a compound of formula(IL), or a salt, solvate, or N-oxide thereof:

wherein R⁵, y, R², individually for each occurrence, and x, individuallyfor each occurrence, have the definitions provided above for Formula I,and G₁ is carbon or nitrogen.

In another embodiment, the compound of formula (II) is a compound offormula (IIb), or a salt, solvate, or N-oxide thereof:

wherein R⁵, y, R², x, and R⁶ have the definitions provided above forFormula I, and wherein the (CH₂)₁₋₆ group can optionally be furthersubstituted with OH, C₁₋₆ alkyl, or OC₁₋₆ alkyl.

In still another embodiment, the compound of formula (II) is a compoundof formula (IIc), or a salt, solvate, or N-oxide thereof:

wherein R⁵, y, R², individually for each occurrence, and x, individuallyfor each occurrence, have the definitions provided above for Formula I,and G₁ is H, alkyl, or substituted alkyl.

In one embodiment, the compound of the invention is a compound offormula (III), or a salt, solvate, or N-oxide thereof:

In one aspect, provided herein are compounds having the Formula IV:

or pharmaceutically acceptable salts thereof;

wherein

R⁴ is H or C₁-C₆ alkyl;

wherein each R⁵ is independently selected at each occurrence from thegroup consisting of CH₃, C₁-C₆ alkoxy, halo, —CN, —NO₂, -(L)_(m)-SR⁹,-(L)_(m)-S(═O)R⁹, -(L)_(m)-S(═O)₂R⁹, -(L)_(m)-NHS(═O)₂R⁹,-(L)_(m)-C(═O)R⁹, -(L)_(m)-OC(═O)R⁹, -(L)_(m)CO₂R⁸, -(L)_(m)-OCO₂R⁸,-(L)_(m)-N(R⁸)₂, -(L)_(m)-C(═O)N(R⁸)₂, -(L)_(m)-OC(═O)N(R⁸)₂,-(L)_(m)-NHC(═O)NH(R⁸), -(L)_(m)-NHC(═O)R⁹, -(L)_(m)-NHC(═O)OR⁹,-(L)_(m)-C(OH)(R⁸)₂, -(L)_(m)C(NH₂)(R⁸)₂, —C₁-C₆ haloalkyl, —C₁-C₆dihaloalkyl and —C₁-C₆ trihaloalkyl;

L is independently, at each occurrence, a bivalent radical selected from—(C₁-C₃ alkylene)-, —(C₃-C₇ cycloalkylene)-, —(C₁-C₃alkylene)_(m)-O—(C₁-C₃ alkylene)_(m)-, or —(C₁-C₃alkylene)_(m)-NH—(C₁-C₃ alkylene)_(m)-;

each R⁸ is independently, at each occurrence, H, C₁-C₆ alkyl, —C₁-C₆haloalkyl, —C₁-C₆ dihaloalkyl, —C₁-C₆ trihaloalkyl, C₁-C₆ heteroalkyl,C₃-C₁₀ cycloalkyl, C₃-C₁₀ heterocycloalkyl, aryl, heteroaryl, —C₁-C₄alkyl-(C₃-C₁₀ cycloalkyl), —C₁-C₄ alkyl-(C₃-C₁₀ heterocycloalkyl),—C₁-C₄ alkyl-(aryl), or —C₁-C₄ alkyl(heteroaryl), and wherein the alkyl,heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl isoptionally substituted with 1-5 substituents selected from R²;

R⁹ is C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ dihaloalkyl, —C₁-C₆trihaloalkyl, C₁-C₆ heteroalkyl, C₃-C₁₀ cycloalkyl, a C₃-C₁₀heterocycloalkyl, aryl, heteroaryl, —C₁-C₄ alkyl-(C₃-C₁₀ cycloalkyl),—C₁-C₄ alkyl-(C₃-C₁₀ heterocycloalkyl), —C₁-C₄ alkyl-(aryl), or —C₁-C₄alkyl-(heteroaryl), and wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl ring is optionally substituted with0-5 substituents selected from R²;

R¹⁰ is OH, C₁-C₆ alkyl, C₁-C₆ alkyl-OH, —C₁-C₆ haloalkyl, —C₁-C₆dihaloalkyl, —C₁-C₆ trihaloalkyl, C₁-C₆ heteroalkyl, C₃-C₁₀ cycloalkyl,a C₃-C₁₀ heterocycloalkyl, aryl, heteroaryl, —C₁-C₄ alkyl-(C₃-C₁₀cycloalkyl), —C₁-C₄ alkyl-(C₃-C₁₀ heterocycloalkyl), —C₁-C₄alkyl-(aryl), or —C₁-C₄ alkyl-(heteroaryl), and wherein the alkyl,heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring isoptionally substituted with 1-5 substituents selected from R²;

R¹¹ is a bond or C₁-C₃ alkylene, wherein the C₁-C₃ alkylene isoptionally substituted with 1-3 substituents selected from R²;

R² is independently selected at each occurrence from the groupconsisting of OH, halo, —CN, —NO₂, —C₁-C₆ alkyl, —C₁-C₆ alkoxy, —C₁-C₆haloalkyl, —C₁-C₆ dihaloalkyl, —C₁-C₆ trihaloalkyl, —C₁-C₆ heteroalkyl,and C(O)—C₁-C₆ alkyl;

w is 0, 1 or 2;

each occurrence of x is independently selected from the group consistingof 0, 1, 2, 3 and 4;

each occurrence of y is independently selected from the group consistingof 1, 2, and 3;

each occurrence of z is independently selected from the group consistingof 0, 1, 2, and 3;

each occurrence of m is independently 0, 1 or 2.

In one embodiment of Formula IV, R² is independently selected at eachoccurrence from the group consisting of halo, —CN, —NO₂, —C₁-C₆ alkyl,—C₁-C₆ alkoxy, —C₁-C₆ haloalkyl, —C₁-C₆ dihaloalkyl, —C₁-C₆trihaloalkyl, —C₁-C₆ heteroalkyl, and C(O)—C₁-C₆ alkyl;

In one embodiment, compounds of Formula IV are of the Formula IVa:

or pharmaceutically acceptable salts thereof.

In embodiments of Formulae IV or IVa,

each R⁵ is independently selected at each occurrence from the groupconsisting of CH₃, C₁-C₆ alkoxy, halo, —CN, —NO₂, —C₁-C₆ haloalkyl,—C₁-C₆ dihaloalkyl, —C₁-C₆ and trihaloalkyl;

R¹⁰ is OH, halo, C₁-C₆ alkyl, C₁-C₆ alkyl-OH, —C₁-C₆ chloroalkyl, —C₁-C₆dichloroalkyl, —C₁-C₆ trichloroalkyl, —C₁-C₆ fluoroalkyl, —C₁-C₆difluoroalkyl, —C₁-C₆ trifluoroalkyl, C₁-C₆ heteroalkyl, C₃-C₁₀cycloalkyl, a C₃-C₁₀ heterocycloalkyl, aryl, heteroaryl, —C₁-C₄alkyl-(C₃-C₁₀ cycloalkyl), —C₁-C₄ alkyl-(C₃-C₁₀ heterocycloalkyl),—C₁-C₄ alkyl-(aryl), or —C₁-C₄ alkyl-(heteroaryl), and wherein thealkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroarylring is optionally substituted with 1-5 substituents selected from R²;

R¹¹ is a bond or C₁-C₃ alkylene, wherein the C₁-C₃ alkylene isoptionally substituted with 1-3 substituents selected from R²;

R² is independently selected at each occurrence from the groupconsisting of halo, —CN, —NO₂, —C₁-C₆ alkyl, —C₁-C₆ alkoxy, —C₁-C₆fluoroalkyl, —C₁-C₆ heteroalkyl, C(O)—C₁-C₆ alkyl, and C(O)—C₁-C₆alkoxy.

In other embodiments of Formulae IV or IVa, each R⁵ is independentlyselected at each occurrence from the group consisting of CH₃, C₁-C₆alkoxy, halo, fluoromethyl, difluoromethyl, trifluoromethyl,chloromethyl, dichloromethyl, and trichloromethyl;

R¹⁰ is OH, halo, C₁-C₆ alkyl, C₁-C₆ alkyl-OH, C₁-C₆ fluoroalkyl, C₁-C₆difluoroalkyl, C₁-C₆ trifluoroalkyl, C₁-C₆ heteroalkyl, C₃-C₁₀cycloalkyl, C₃-C₁₀ heterocycloalkyl, aryl, heteroaryl, —C₁-C₄alkyl-(C₃-C₁₀ cycloalkyl), —C₁-C₄ alkyl-(C₃-C₁₀ heterocycloalkyl),—C₁-C₄ alkyl-(aryl), or —C₁-C₄ alkyl-(heteroaryl), and wherein thealkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroarylring is optionally substituted with 1-5 substituents selected from R²;

R¹¹ is a bond or C₁-C₃ alkylene;

R² is independently selected at each occurrence from the groupconsisting of halo, —CN, —NO₂, —C₁-C₆ alkyl, —C₁-C₆ alkoxy, —C₁-C₆fluoroalkyl, —C₁-C₆ heteroalkyl, and C(O)—C₁-C₆ alkyl, and C(O)—C₁-C₆alkoxy.

In other embodiments of Formulae IV and IVa, R⁵ (i.e., (R⁵)_(y)) is 3-F,3-Cl, 3-CH₃, 3-CH₂F, 3-CHF₂, 4-F, 3-CH₃-4-F, 3-Cl-4-F, 3-Br-4-F,3,4,5-trifluoro, 3,4,5-trichloro, or 3-chloro-4,5-difluoro. In anotherembodiment, w is 1 or 2.

In yet other embodiments of Formulae IV and IVa,

R¹¹ is a bond or C₁-C₃ alkylene;

R¹⁰ is OH, halo, C₁-C₆ alkyl, C₁-C₆ alkyl-OH, —C₁-C₆ chloroalkyl, —C₁-C₆dichloroalkyl, —C₁-C₆ trichloroalkyl, —C₁-C₆ fluoroalkyl, —C₁-C₆difluoroalkyl, —C₁-C₆ trifluoroalkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀heterocycloalkyl, or phenyl, wherein the C₃-C₁₀ cycloalkyl, a C₃-C₁₀heterocycloalkyl, or phenyl groups are optionally substituted with 1-5substituents selected from halo, —C₁-C₆ alkyl, and —C₁-C₆ alkoxy; and

z is 0 or 1.

In another embodiment, compounds of Formula IV are of the Formula IVb:

or pharmaceutically acceptable salts thereof;

wherein G¹ is independently selected at each occurrence from CH₃, OCH₃,halo, CF₃, CCl₃, CH₂Cl, CCl₂H, CF₂H, CH₂F, and CF₃;

G² is H, C₁-C₄ alkyl, or halo;

G³ is OH, CH₂OH, or CH₂CH₂OH;

G⁴ is H, OH, halo, C₁-C₆ alkyl, C₁-C₆ alkyl-OH, —C₁-C₆ chloroalkyl,—C₁-C₆ dichloroalkyl, —C₁-C₆ trichloroalkyl, —C₁-C₆ fluoroalkyl, —C₁-C₆difluoroalkyl, —C₁-C₆ trifluoroalkyl, or phenyl, wherein the phenylgroup is optionally independently substituted with 1-5 substituentsselected from halo, —C₁-C₆ alkyl, and —C₁-C₆ alkoxy; and

y is 1, 2, or 3.

In an embodiment of Formula IVb, wherein G¹ is independently selected ateach occurrence from halo, CF₃, CCl₃, CH₂Cl, CCl₂H, CF₂H, CH₂F, and CF₃;

In another embodiment, compounds of Formula IV are of the Formula IVc:

or pharmaceutically acceptable salts thereof;

wherein X is halo;

G¹ is hydrogen or halo;

G² is H, C₁-C₄ alkyl, or halo; and

G⁴ is H, halo, C₁-C₄ alkyl, or OH.

In one embodiment of Formula IVc, G² is C₁-C₄ alkyl or halo, and whereinG² is in the 2, 3, or 4 position of the phenyl ring.

In another aspect, provided herein are compounds of the Formula V:

or pharmaceutically acceptable salts thereof;

wherein

R⁴ is H or C₁-C₆ alkyl;

G¹ is H or C₁-C₆ alkyl;

wherein each R⁵ is independently selected at each occurrence from thegroup consisting of —C₁-C₆ alkyl, halo, —CN, —NO₂, -(L)_(m)-OR⁸,-(L)_(m)-SR⁹, -(L)_(m)-S(═O)R⁹, -(L)_(m)-S(═O)₂R⁹, -(L)_(m)-NHS(═O)₂R⁹,-(L)_(m)-C(═O)R⁹, -(L)_(m)-OC(═O)R⁹, -(L)_(m)CO₂R⁸, -(L)_(m)-OCO₂R⁸,-(L)_(m)-CH(R⁸)₂, -(L)_(m)-N(R⁸)₂, -(L)_(m)-C(═O)N(R⁸)₂,-(L)_(m)-OC(═O)N(R⁸)₂, -(L)_(m)-NHC(═O)NH(R⁸), -(L)_(m)-NHC(═O)R⁹,-(L)_(m)-NHC(═O)OR⁹, -(L)_(m)-C(OH)(R⁸)₂, -(L)_(m)C(NH₂)(R⁸)₂, —C₁-C₆haloalkyl, —C₁-C₆ dihaloalkyl and —C₁-C₆ trihaloalkyl;

L is independently, at each occurrence, a bivalent radical selected from—(C₁-C₃ alkylene)-, —(C₃-C₇ cycloalkylene)-, —(C₁-C₃alkylene)_(m)-O—(C₁-C₃ alkylene)_(m)-, or —(C₁-C₃alkylene)_(m)-NH—(C₁-C₃ alkylene)_(m)-;

each R⁸ is independently, at each occurrence, H, C₁-C₆ alkyl, —C₁-C₆haloalkyl, —C₁-C₆dihaloalkyl, —C₁-C₆ trihaloalkyl, C₁-C₆ heteroalkyl,C₃-C₁₀ cycloalkyl, C₃-C₁₀ heterocycloalkyl, aryl, heteroaryl, —C₁-C₄alkyl-(C₃-C₁₀ cycloalkyl), —C₁-C₄ alkyl-(C₃-C₁₀ heterocycloalkyl),—C₁-C₄ alkyl-(aryl), or —C₁-C₄ alkyl(heteroaryl), and wherein the alkyl,heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl isoptionally substituted with 1-5 substituents selected from R²;

R⁹ is C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ dihaloalkyl, —C₁-C₆trihaloalkyl, C₁-C₆ heteroalkyl, C₃-C₁₀ cycloalkyl, a C₃-C₁₀heterocycloalkyl, aryl, heteroaryl, —C₁-C₄ alkyl-(C₃-C₁₀ cycloalkyl),—C₁-C₄ alkyl-(C₃-C₁₀ heterocycloalkyl), —C₁-C₄ alkyl-(aryl), or —C₁-C₄alkyl-(heteroaryl), and wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl ring is optionally substituted with1-5 substituents selected from R²;

R² is independently selected at each occurrence from the groupconsisting of halo, —OH, —CN, —NO₂, —C₁-C₆ alkyl, —C₁-C₆ alkoxy, —C₁-C₆fluoroalkyl, —C₁-C₆ heteroalkyl, and C(O)—C₁-C₆ alkyl;

n is 1, 2, 3, 4, 5, or 6;

each occurrence of x is independently selected from the group consistingof 0, 1, 2, 3 and 4;

each occurrence of y is independently selected from the group consistingof 1, 2, and 3; and

each occurrence of m is independently 0, 1 or 2.

In one embodiment of Formula (V),

each R⁵ is independently selected at each occurrence from the groupconsisting of OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, halo, —CN, —NO₂, C₁-C₆chloroalkyl, —C₁-C₆ dichloroalkyl, —C₁-C₆ trichloroalkyl, —C₁-C₆fluoroalkyl, —C₁-C₆ difluoroalkyl and —C₁-C₆ trifluoroalkyl; and

R² is independently selected at each occurrence from the groupconsisting of halo, —OH, —CN, —NO₂, —C₁-C₆ alkyl, —C₁-C₆ alkoxy, —C₁-C₆fluoroalkyl, —C₁-C₆ heteroalkyl, and C(O)—C₁-C₆ alkyl.

In another embodiment of Formula (V),

each R⁵ is independently selected at each occurrence from the groupconsisting of —OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, halo, fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, andtrichloromethyl;

R² is independently selected at each occurrence from the groupconsisting of —OH, halo, —CN, —NO₂, —C₁-C₆ alkyl, —C₁-C₆ alkoxy, —C₁-C₆fluoroalkyl, —C₁-C₆ heteroalkyl, and C(O)—C₁-C₆ alkyl.

In still another embodiment of Formula (V),

each R⁵ is independently selected at each occurrence from the groupconsisting of —OH, C₁-C₆ alkyl, halo, fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, and trichloromethyl; and

each R² is independently selected at each occurrence from the groupconsisting of halo, —C₁-C₆ alkyl, or —C₁-C₆ alkoxy.

In another aspect, provided herein are compounds of Formula VI:

or pharmaceutically acceptable salts thereof;

wherein

R⁴ is H or C₁-C₆ alkyl;

G¹ is H or C₁-C₆ alkyl;

wherein each R⁵ is independently selected at each occurrence from thegroup consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, halo, —CN, —NO₂,-(L)_(m)-SR⁹, -(L)_(m)-S(═O)R⁹, -(L)_(m)-S(═O)₂R⁹, -(L)_(m)-NHS(═O)₂R⁹,-(L)_(m)-C(═O)R⁹, -(L)_(m)-OC(═O)R⁹, -(L)_(m)CO₂R⁸, -(L)_(m)-OCO₂R⁸,-(L)_(m)-CH(R⁸)₂, -(L)_(m)-N(R⁸)₂, -(L)_(m)-C(═O)N(R⁸)₂,-(L)_(m)-OC(═O)N(R⁸)₂, -(L)_(m)-NHC(═O)NH(R⁸), -(L)_(m)-NHC(═O)R⁹,-(L)_(m)-NHC(═O)OR⁹, -(L)_(m)-C(OH)(R⁸)₂, -(L)_(m)C(NH₂)(R⁸)₂, —C₁-C₆haloalkyl, —C₁-C₆ dihaloalkyl and —C₁-C₆ trihaloalkyl;

L is independently, at each occurrence, a bivalent radical selected from—(C₁-C₃ alkylene)-, —(C₃-C₇ cycloalkylene)-, —(C₁-C₃alkylene)_(m)-O—(C₁-C₃ alkylene)_(m)-, or —(C₁-C₃alkylene)_(m)-NH—(C₁-C₃ alkylene)_(m)-;

each R⁸ is independently, at each occurrence, H, C₁-C₆ alkyl, —C₁-C₆haloalkyl, —C₁-C₆dihaloalkyl, —C₁-C₆ trihaloalkyl, C₁-C₆ heteroalkyl,C₃-C₁₀ cycloalkyl, C₃-C₁₀ heterocycloalkyl, aryl, heteroaryl, —C₁-C₄alkyl-(C₃-C₁₀ cycloalkyl), —C₁-C₄ alkyl-(C₃-C₁₀ heterocycloalkyl),—C₁-C₄ alkyl-(aryl), or —C₁-C₄ alkyl(heteroaryl), and wherein the alkyl,heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl isoptionally substituted with 1-5 substituents selected from R²;

R⁹ is C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ dihaloalkyl, —C₁-C₆trihaloalkyl, C₁-C₆ heteroalkyl, C₃-C₁₀ cycloalkyl, a C₃-C₁₀heterocycloalkyl, aryl, heteroaryl, —C₁-C₄ alkyl-(C₃-C₁₀ cycloalkyl),—C₁-C₄ alkyl-(C₃-C₁₀ heterocycloalkyl), —C₁-C₄ alkyl-(aryl), or —C₁-C₄alkyl-(heteroaryl), and wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl ring is optionally substituted with1-5 substituents selected from R²;

R¹⁰ is OH, C₁-C₆ alkyl, C₁-C₆ alkyl-OH, C₁-C₆ fluoroalkyl, C₁-C₆heteroalkyl, C₃-C₁₀ cycloalkyl, a C₃-C₁₀ heterocycloalkyl, aryl,heteroaryl, —C₁-C₄ alkyl-(C₃-C₁₀ cycloalkyl), —C₁-C₄ alkyl-(C₃-C₁₀heterocycloalkyl), —C₁-C₄ alkyl-(aryl), or —C₁-C₄ alkyl-(heteroaryl),and wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylor heteroaryl ring is optionally substituted with 1-5 substituentsselected from R²;

R¹¹ is a bond or C₁-C₃ alkylene, wherein the C₁-C₃ alkylene isoptionally substituted with 1-3 substituents selected from R²;

R² is independently selected at each occurrence from the groupconsisting of halo, —CN, —NO₂, —C₁-C₆ alkyl, —C₁-C₆ alkoxy, —C₁-C₆fluoroalkyl, —C₁-C₆ heteroalkyl, and C(O)—C₁-C₆ alkyl;

w is 0, 1 or 2;

each occurrence of x is independently selected from the group consistingof 0, 1, 2, 3 and 4;

each occurrence of y is independently selected from the group consistingof 0, 1, 2, 3 and 4;

each occurrence of z is independently selected from the group consistingof 0, 1, 2, and 3;

each occurrence of m is independently 0, 1 or 2.

In certain embodiments of Formula VI,

each R⁵ is independently selected at each occurrence from the groupconsisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, halo, —CN, —NO₂, —C₁-C₆haloalkyl, —C₁-C₆ dihaloalkyl, and —C₁-C₆ trihaloalkyl;

R¹⁰ is OH, halo, C₁-C₆ alkyl, C₁-C₆ alkyl-OH, —C₁-C₆ haloalkyl, —C₁-C₆dihaloalkyl, —C₁-C₆ trihaloalkyl, C₁-C₆ heteroalkyl, C₃-C₁₀ cycloalkyl,a C₃-C₁₀ heterocycloalkyl, aryl, heteroaryl, —C₁-C₄ alkyl-(C₃-C₁₀cycloalkyl), —C₁-C₄ alkyl-(C₃-C₁₀ heterocycloalkyl), —C₁-C₄alkyl-(aryl), or —C₁-C₄ alkyl-(heteroaryl), and wherein the alkyl,heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring isoptionally substituted with 1-5 substituents selected from R²;

R¹¹ is a bond or C₁-C₃ alkylene, wherein the C₁-C₃ alkylene isoptionally substituted with 1-3 substituents selected from R²;

R² is independently selected at each occurrence from the groupconsisting of halo, —CN, —NO₂, —C₁-C₆ alkyl, —C₁-C₆ alkoxy, —C₁-C₆fluoroalkyl, —C₁-C₆ heteroalkyl, C(O)—C₁-C₆ alkyl, and C(O)—C₁-C₆alkoxy.

In another embodiment of Formula VI,

each R⁵ is independently selected at each occurrence from the groupconsisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, halo, fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, andtrichloromethyl;

R¹⁰ is OH, halo, C₁-C₆ alkyl, C₁-C₆ alkyl-OH, C₁-C₆ fluoroalkyl, C₁-C₆difluoroalkyl, C₁-C₆ trifluoroalkyl, C₁-C₆ heteroalkyl, C₃-C₁₀cycloalkyl, a C₃-C₁₀ heterocycloalkyl, aryl, heteroaryl, —C₁-C₄alkyl-(C₃-C₁₀ cycloalkyl), —C₁-C₄ alkyl-(C₃-C₁₀ heterocycloalkyl),—C₁-C₄ alkyl-(aryl), or —C₁-C₄ alkyl-(heteroaryl), and wherein thealkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroarylring is optionally substituted with 1-5 substituents selected from R²;

R¹¹ is a bond or C₁-C₃ alkylene;

R² is independently selected at each occurrence from the groupconsisting of halo, —CN, —NO₂, —C₁-C₆ alkyl, —C₁-C₆ alkoxy, —C₁-C₆fluoroalkyl, —C₁-C₆ heteroalkyl, and C(O)—C₁-C₆ alkyl, and C(O)—C₁-C₆alkoxy.

In other embodiments of Formula VI, R⁵ is 3-F, 3-Cl, 3-CH₃, 3-CH₂F,3-CHF₂, 4-F, 3-CH₃-4-F, 3-Cl-4-F, 3-Br-4-F, 3,4,5-trifluoro,3,4,5-trichloro, or 3-chloro-4,5-difluoro. In another embodiment, w is 1or 2.

In still another embodiment of Formula VI,

R¹¹ is a bond or C₁-C₃ alkylene;

R¹⁰ is OH, halo, C₁-C₆ alkyl, C₁-C₆ alkyl-OH, —C₁-C₆ chloroalkyl, —C₁-C₆dichloroalkyl, —C₁-C₆ trichloroalkyl, —C₁-C₆ fluoroalkyl, —C₁-C₆difluoroalkyl, —C₁-C₆ trifluoroalkyl, C₃-C₁₀ cycloalkyl, a C₃-C₁₀heterocycloalkyl, or phenyl, wherein the C₃-C₁₀ cycloalkyl, a C₃-C₁₀heterocycloalkyl, or phenyl groups are optionally substituted with 1-5substituents selected from halo, —C₁-C₆ alkyl, and —C₁-C₆ alkoxy; and

z is 0 or 1.

In an embodiment, compounds of Formula VI are of the Formula VIa:

or pharmaceutically acceptable salts thereof;

wherein G¹ is independently selected at each occurrence from CH₃, OCH₃,halo, CF₃, CCl₃, CH₂Cl, CCl₂H, CF₂H, CH₂F, and CF₃;

G² is H, C₁-C₄ alkyl, or halo;

G³ is OH, CH₂OH, or CH₂CH₂OH;

G⁴ is H, OH, halo, C₁-C₆ alkyl, C₁-C₆ alkyl-OH, —C₁-C₆ chloroalkyl,—C₁-C₆ dichloroalkyl, —C₁-C₆ trichloroalkyl, —C₁-C₆ fluoroalkyl, —C₁-C₆difluoroalkyl, —C₁-C₆ trifluoroalkyl, or phenyl, wherein the phenylgroup is optionally independently substituted with 1-5 substituentsselected from halo, —C₁-C₆ alkyl, and —C₁-C₆ alkoxy; and

y is 1, 2, or 3.

In an embodiment, compounds of Formula VI are of the Formula VIaa:

or pharmaceutically acceptable salts thereof;

wherein G¹ is independently selected at each occurrence from C₁-C₆alkyl,OC₁-C₆alkyl, halo, CF₃, CCl₃, CH₂C1, CCl₂H, CF₂H, CH₂F, and CF₃;

G² is H, C₁-C₄ alkyl, or halo;

G³ is OH, CH₂OH, or CH₂CH₂OH;

G⁴ is H, OH, halo, C₁-C₆ alkyl, C₁-C₆ alkyl-OH, —C₁-C₆ chloroalkyl,—C₁-C₆ dichloroalkyl, —C₁-C₆ trichloroalkyl, —C₁-C₆ fluoroalkyl, —C₁-C₆difluoroalkyl, —C₁-C₆ trifluoroalkyl, or phenyl, wherein the phenylgroup is optionally independently substituted with 1-5 substituentsselected from halo, —C₁-C₆ alkyl, and —C₁-C₆ alkoxy; and

y is 1, 2, or 3.

In another embodiment, compounds of Formula VI are of the Formula VIb:

or pharmaceutically acceptable salts thereof;

wherein X is halo;

G¹ is hydrogen or halo;

G² is H, C₁-C₄ alkyl, or halo; and

G⁴ is H, halo, C₁-C₄ alkyl, or OH.

In another aspect, provided herein is a compound of Formula VII:

or pharmaceutically acceptable salts thereof;

wherein

R⁴ is H or C₁-C₆ alkyl;

wherein each R⁵ is independently selected at each occurrence from thegroup consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, halo, —CN, —NO₂,-(L)_(m)-SR⁹, -(L)_(m)-S(═O)R⁹, -(L)_(m)-S(═O)₂R⁹, -(L)_(m)-NHS(═O)₂R⁹,-(L)_(m)-C(═O)R⁹, -(L)_(m)-OC(═O)R⁹, -(L)_(m)CO₂R⁸, -(L)_(m)-OCO₂R⁸,-(L)_(m)-CH(R⁸)₂, -(L)_(m)-N(R⁸)₂, -(L)_(m)-C(═O)N(R⁸)₂,-(L)_(m)-OC(═O)N(R⁸)₂, -(L)_(m)-NHC(═O)NH(R⁸), -(L)_(m)-NHC(═O)R⁹,-(L)_(m)-NHC(═O)OR⁹, -(L)_(m)-C(OH)(R⁸)₂, -(L)_(m)C(NH₂)(R⁸)₂, —C₁-C₆haloalkyl, —C₁-C₆ dihaloalkyl and —C₁-C₆ trihaloalkyl;

L is independently, at each occurrence, a bivalent radical selected from—(C₁-C₃ alkylene)-, —(C₃-C₇ cycloalkylene)-, —(C₁-C₃alkylene)_(m)-O—(C₁-C₃ alkylene)_(m)-, or —(C₁-C₃alkylene)_(m)-NH—(C₁-C₃ alkylene)_(m)-;

each R⁸ is independently, at each occurrence, H, C₁-C₆ alkyl, —C₁-C₆haloalkyl, —C₁-C₆ dihaloalkyl, —C₁-C₆ trihaloalkyl, C₁-C₆ heteroalkyl,C₃-C₁₀ cycloalkyl, C₃-C₁₀ heterocycloalkyl, aryl, heteroaryl, —C₁-C₄alkyl-(C₃-C₁₀ cycloalkyl), —C₁-C₄ alkyl-(C₃-C₁₀ heterocycloalkyl),—C₁-C₄ alkyl-(aryl), or —C₁-C₄ alkyl(heteroaryl), and wherein the alkyl,heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl isoptionally substituted with 1-5 substituents selected from R²;

R⁹ is C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ dihaloalkyl, —C₁-C₆trihaloalkyl, C₁-C₆ heteroalkyl, C₃-C₁₀ cycloalkyl, a C₃-C₁₀heterocycloalkyl, aryl, heteroaryl, —C₁-C₄ alkyl-(C₃-C₁₀ cycloalkyl),—C₁-C₄ alkyl-(C₃-C₁₀ heterocycloalkyl), —C₁-C₄ alkyl-(aryl), or —C₁-C₄alkyl-(heteroaryl), and wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl ring is optionally substituted with1-5 substituents selected from R²;

R¹⁰ is H, C₁-C₆ alkyl, -(L)_(m)-C(═O)C₁-C₆ alkyl, -(L)_(m)-C(═O)C₃-C₁₀cycloalkyl, -(L)_(m)-C(═O)OC₁-C₆ alkyl, -(L)_(m)-C(═O)OC₃-C₁₀ cycloalkylwherein the alkyl or cycloalkyl groups are optionally substituted withhalo, —C₁-C₆ haloalkyl, —C₁-C₆ dihaloalkyl, or —C₁-C₆ trihaloalkyl;

R¹¹ is a bond or C₁-C₃ alkylene, wherein the C₁-C₃ alkylene isoptionally substituted with 0-3 substituents selected from R²;

R² is independently selected at each occurrence from the groupconsisting of halo, —CN, —NO₂, —C₁-C₆ alkyl, —C₁-C₆ alkoxy, —C₁-C₆fluoroalkyl, —C₁-C₆ heteroalkyl, and C(O)—C₁-C₆ alkyl;

each occurrence of x is independently selected from the group consistingof 0, 1, 2, 3, or 4;

each occurrence of y is independently selected from the group consistingof 1, 2, and 3;

z is 0 or 1; and

each occurrence of m is independently 0, 1 or 2.

In one embodiment of Formula VII, each R⁵ is independently selected ateach occurrence from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy,halo, —CN, —NO₂, —C₁-C₆haloalkyl, —C₁-C₆ dihaloalkyl, and —C₁-C₆trihaloalkyl;

R¹¹ is a bond or C₁-C₃ alkylene, wherein the C₁-C₃ alkylene isoptionally substituted with 0-3 substituents selected from R²;

R² is independently selected at each occurrence from the groupconsisting of halo, —CN, —NO₂, —C₁-C₆ alkyl, —C₁-C₆ alkoxy, —C₁-C₆fluoroalkyl, —C₁-C₆ heteroalkyl, C(O)—C₁-C₆ alkyl, and C(O)—C₁-C₆alkoxy.

In an embodiment of Formula VII,

each R⁵ is independently selected at each occurrence from the groupconsisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, halo, fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, andtrichloromethyl;

R¹¹ is a bond or C₁-C₃ alkylene;

R² is independently selected at each occurrence from the groupconsisting of halo, —CN, —NO₂, —C₁-C₆ alkyl, —C₁-C₆ alkoxy, —C₁-C₆fluoroalkyl, —C₁-C₆ heteroalkyl, and C(O)—C₁-C₆ alkyl, and C(O)—C₁-C₆alkoxy.

In an embodiment of Formula VII, R⁵ is 3-F, 3-Cl, 3-CH₃, 3-CH₂F, 3-CHF₂,4-F, 3-CH₃-4-F, 3-Cl-4-F, 3-Br-4-F, 3,4,5-trifluoro, 3,4,5-trichloro, or3-chloro-4,5-difluoro. In another embodiment, R² is H, C₁-C₄ alkyl, orhalo. In still another embodiment, R¹⁰ is C(═O)C₃-C₁₀ cycloalkyl,wherein the or cycloalkyl group is optionally substituted with halo,—C₁-C₆ haloalkyl, —C₁-C₆ dihaloalkyl, or —C₁-C₆ trihaloalkyl.

It will be appreciated that the description of the present inventionherein should be construed in congruity with the laws and principals ofchemical bonding. In some instances it may be necessary to remove ahydrogen atom in order to accommodate a substitutent at any givenlocation.

It is noted for the generic structures described herein that rings thatare substituted by two or more variables (R groups, G groups, etc.) canindicate, for example, either viscinal (e.g., compounds 960D1 and 960D2)or geminal (e.g., compound 916) substitution patterns.

Preferred embodiments of Formulas I-VII, including pharmaceuticallyacceptable salts thereof, as well as enantiomers, stereoisomers,rotamers, tautomers, diastereomers, atropisomers or racemates thereof,and are shown below in Table 1 and are also considered to be “compoundsof the invention.” (Some compounds of Table 1 do not include hydrogenson hydroxyl groups; it is understood that “—O” indicates a hydroxylsubstituent at these positions.)

Synthetic method codes refer to the synthesis methodologies provided inthe experimental section. For example, “A19B03C15” refers the use ofintermediate A19 for region A, intermediate B03 for region B, andintermediate C15 for region C, and “GA” refers to general synthesisprocedures G and A.

TABLE 1 Structure MS(M + H)⁺ Cmp. Synthetic method ID

 001

 002

 005

 006

 013

 014

 015

 016

 021

 022

 025

 026

 033

 034

 037

 038

 041

 042

 049

 050

 053

 054

 061

 062

 063

 064

 065

 066

 071

 072

 073

 074

 075

 076

 077

 078

 079

 080

 081

 082

 083

 084

 097

 098

 099

 100

 103

 104

 115

 116

 117

 118

 119

 120

 121

 122

 123

 124

 125

 126

 127

 128

 129

 130

 131

 132

 135

 136

 141

 142

 147

 148

 151

 152

 159

 160

 168

 169

 170

 171

 174

 175

 176

 177

 178

 179

 180

 181

 182

 183

 184

 186

 191

 192

 201

 206

 208

 210

 212

 215

 216

 217

 217_R

 217_S

 219

 224

 225

 226

 227

 228

 229

 230

 231

 233

 234

 238

 244

 245

 250

 251

 254

 258

 263

 264

 269

 270

 271

 274

 278

 278_E1

 278_E2

 284

 285

 290

 291

 291_E1

 291_E2

 294

 298

 302

 304

 305

 306

 309 438 GB A10B01C45 ¹H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 8.67(m, 1H), 8.33 (m, 2H), 8.21 (m, 1H), 7.96 (m, 1H), 7.87 (m, 2H), 7.68(m, 2H), 7.57 (m, 2H), 3.53 (m, 2H), 3.18 (m, 3H), 2.68 (m, 2H), 1.77(m, 2H), 1.45 (m, 2H)

 310

 311

 314

 318

 321

 322

 328

 329

 331

 332

 335

 336

 337

 338

 341

 342

 343

 345

 347

 348

 351

 352

 355

 356

 357

 358

 359

 360

 361

 363

 366

 371

 372

 373

 374

 375

 376

 380

 383

 386

 387

 388

 390

 391

 392

 395

 396

 398

 401

 404

 405

 406

 407

 408

 410

 411

 412

 415

 417

 418

 419

 420

 425

 427

 428

 435

 436

 438

 441

 447

 448

 455

 458

 463

 467

 468

 471

 472

 473

 474

 477

 478

 479

 482

 489

 501

 502

 503

 505

 506

 507

 520

 521

 522

 523

 524

 526

 527

 528

 529

 530

 531

 541

 544

 545

 546

 547

 553

 554

 555

 558

 559

 568

 569

 577

 578

 579

 583

 587

 589

 593

 594

 595

 596-D1

 596-D2

 597_D1

 597_D2

 601_D1

 601_D2

 608_D1

 608_D2

 610_D1

 610_D2

 615_D1

 615_D2

 620

 621

 622

 623

 624

 625

 626

 627

 628

 629

 630

 631

 632_R

 632_S

 633

 634

 641

 642

 644_D2

 645

 646

 647_R

 649

 650

 651

 652

 655

 661

 662_R

 662_S

 663

 664

 667

 668

 675

 676

 677_R

 677_S

 678

 679 429 GA A10B01C62 ¹H NMR (400 MHz, CDCl₃) 8.23 (s, 1H), 8.17-8.18(d, 2H), 7.95-7.97 (d, J = 8.0 Hz, 1H), 7.88-7.89 (d, J = 5.2 Hz, 2H),7.40-7.74 (m, 1H), 7.18-7.23 (t, J = 18.8 Hz, 1H), 6.79-7.07 (t, J =29.6 Hz 1H), 3.82-3.85 (m, 1H), 3.30-3.35 (m, 2H), 2.96-3.02 (m, 2H),1.92-1.98 (m, 2H), 1.61-1.73 (m, 2H), 1.42 (s, 1H).

 680

 690

 694

 695

 696

 700_R

 700_S

 705

 706

 708

 709

 712

 713_D1

 713-D2

 714_D1

 715_D2

 716_D1

 719_D1

 719_D2

 720_D1

 720_D2

 721_D1

 724_D2

 725_D1

 725_D2

 726_D1

 726_D2

 727_D1

 727_D2

 729_D2

 731

 741

 742

 743_D1

 743_D2

 747_D1

 747_D2

 748_D1

 748_D2

 749_D1

 749_D2

 751_D1

 751_D2

 753

 754

 755

 756_D1

 756_D2

 757

 758

 759

 760

 761

 765 509 GA A97B01C40 1H NMR (400 MHz, DMSO) δ 10.85 (s, 1H), 8.31 (t, J= 2 Hz, 2H), 8.04 (d, J = 8.0 Hz, 1H), 7.90 (t, J = 8.0 Hz, 1H), 7.74(dd, J = 6.8, 10.4 Hz, 2H), 7.47 (m, 2H), 7.13 (t, J = 8.8 Hz, 2H), 5.03(s, 1H), 3.62 (d, J = 10.8 Hz, 2H), 2.62 (t, J = 10.8 Hz, 2H), 1.99 (m,2H), 1.66 (d, J = 13.2 Hz, 2H).

 766 509 GA A98B01C40 1H NMR (400 MHz, DMSO) δ 1H NMR (400 MHz, DMSO) δ8.31 (m, 2H), 8.04 (d, J = 7.4 Hz, 1H), 7.90 (t, J = 8.0 Hz, 1H), 7.74(dd, J = 6.8, 10.4 Hz, 2H), 7.47 (m, 2H), 7.03 (m, 1H), 5.11 (s, 1H),3.62 (d, J = 11.2 Hz, 2H), 2.62 (t, J = 11.2 Hz, 2H), 2.03 (dt, J = 4.0,12.8 Hz, 2H), 1.66 (d, J = 12.8 Hz, 2H).

 767

 768 527 GA A100B01C40 1H NMR (400 MHz, MeOD) δ 10.38 (m, 1H), 8.26 (d,J = 7.6 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.83 (t, J = 8.0 Hz, 1H),7.65 (m, 2H), 7.38 (m, 1H), 7.26 (m, 2H), 3.76 (dd, J = 2, 9.2 Hz, 2H),2.62 (dt, J = 2, 12 Hz, 2H), 2.23 (dt, J = 4.8, 9.2 Hz, 2H), 1.66 (d, J= 12.4 Hz, 2H).

 769

 770

 771

 772

 773 507/509 GA A99B01C15 1H NMR (400 MHz, DMSO) δ 10.73 (s, 1H), 8.33(m, 2H), 8.08 (dd, J = 2.8, 6.8 Hz, 1H), 8.03 (d, J = 6.8 Hz, 1H), 7.90(t, J = 8.0 Hz, 1H), 7.75 (m, 1H), 7.57 (m, 1H), 7.46 (t, J = 9.2 Hz,1H), 7.29 (m, 1H), 7.16 (m, 2H), 5.23 (s, 1H), 3.62 (d, J = 10.8 Hz,2H), 2.62 (t, J = 10.8 Hz, 2H), 2.23 (m, 2H), 1.66 (d, J = 13.2 Hz, 2H).

 774 525/527 GA A100B01C15 1H NMR (400 MHz, MeOD) δ 8.46 (s, 1H), 8.27(d, J = 8.0 Hz, 1H), 8.03 (m, 2H), 7.82 (t, J = 8.0 Hz, 1H), 7.68 (m,1H), 7.37 (m, 1H), 7.24 (m, 3H), 3.76 (dd, J = 2, 8.8 Hz, 2H), 2.62 (dt,J = 2, 12 Hz, 2H), 2.13 (dt, J = 4.4, 13.2 Hz, 2H), 1.77 (d, J = 12.4Hz, 2H).

 775

 776

 777

 785

 786

 787_D1

 787_D2

 792 449 GA A96B01C20 ¹H NMR (400 MHz, CDCl₃) 8.25 (s, 1H), 8.00-8.12(m, 1H), 7.94-7.98 (m, 2H), 7.66- 7.70 (m, 1H), 7.55-7.56 (m, 1H),7.42-7.44 (m, 1H), 7.02-7.07 (t, J = 17.6 Hz, 1H), 3.86- 3.92 (m, 1H),3.18-3.38 (m, 2H), 3.16 (s, 3H), 3.12-3.20 (m, 1H), 2.93-2.99 (m, 1H),2.33- 2.35 (d, J = 1.6 Hz, 3H), 1.72-1.82 (m, 2H), 1.50-1.55 (m, 3H),1.49-1.58 (m, 5H).

 793

 797

 799

 803

 804_R

 804_S

 805

 806

 807

 808

 809

 810

 818_D2

 819_D1

 819_D2

 820_D1

 820_D2

 821_D1

 821_D2

 822_D1

 822_D2

 824_D1

 824_D2

 825_D1

 825_D2

 826

 827

 828

 829

 830

 834_D1

 835

 843

 844

 846

 847

 848

 849

 854

 851

 862

 863

 867_D1

 867_D2

 868_D1

 871_D1

 871_D2

 872_D1

 872_D2

 875

 876

 878

 879

 881

 882

 883

 884

 885

 886

 887

 888

 889

 890

 891

 892

 893

 894

 895

 896

 898_D1

 898_D2

 899_D1

 899_D2

 900

 901

 902

 903

 904_R

 904_S

 907

 908

 916

 917

 910

 911

 912_D1

 912_D2

 913_D1

 913_D2

 914

 919

 922

 923_D1

 923_D2

 924

 925

 927

 931

 935

 928

 932_D1

 933_D1

 940_D1

 940_D2

 943_D1

 942

 943_D2

 945_D2

 946_D1

 946_D2

 952

 953

 954

 955_D1

 955_D2

 956

 957

 958

 959

 960_D1

 960_D2

 961

 962_D1

 962_D2

 963_D1

 963_D2

 964_D1

 964_D2

 972_D1

 972_D2

 973_D1

 973_D2

 976_D1

 977_D2

 978_CT1

 978_CT2

 979_CT1

 981_CT2

 981_D1

 990_D1

 988_D1

 988_D2

 990_D2

 998_D1

 998_D2

1007

1008

1017

1018

1019

1021

1022

1033

1057

1058

1059

1060

1061

1062

1070

1078_D1

1078_D2

1079

1081_D1

1081_D2

1089

1090

1095_R

1095_S

1096_R

1096_S

1098

1099

1107

1114

1116

1126

1130

1134_CT1

1134_CT2

1135_D1

1135_D2

1149

1150

1154

1157

1161

1170_D1

1170_D2

1178

1182

1194

1198

1201

1202

1205

1206

1207

1208

1209_CT1

1209_CT2

1231

1241

1242

1249

1250

1251

1253

1255

1257

1261

1263

1273_D1

1273_D2

1275

1281_D1

1281_D2

1001_D1

1001_D2

1002_D1

1002_D2

1003_D1

1003_D2

1004_D1

1004_D2

1005_D1

1005_D2

1006_D1

1006_D2

1009

1010

1011

1020

1023

1024

1025

1026

1027

1028

1029_D1

1029_D2

1030_D1

1030_D2

1031_D1

1031_D2

1032_D1

1032_D2

1033

1034

1035

1036

1037

1038

1039

1040

1041

1042

1043

1044

1049

1050

1051

1052

1053

1054

1055

1056_D2

1057

1061

1063

1064

1065

1066

1067

1068

1069

1070

1071

1073

1074

1075

1076

1077_D1

1077_D2

1080

1082_D1

1082_D2

1083_D1

1084_D1

1084_D2

1085

1086

1087

1088

1091

1092

1093_R

1093_S

1094_R

1094_S

1100

1101

1102

1103

1104

1105

1106

1108

1109

1110

1111

1112

1113

1115

1433

1117

1118

1119

1120

1121_D1

1121_D2

1122_D1

1122_D2

1123_D1

1123_D2

1124_D1

1124_D2

1125

1126

1127

1128

1129

1444

1131_D1

1131_D2

1132_D1

1132_D2

1133

1445

1136_CT1

1136_CT2

1141

1142

1143

1144

1146

1147

1148

1151

1152

1153

1155

1156

1421

1158

1160

1422

1162

1163

1164

1165

1166

1167

1168

1169_D1

1169_D2

1171_D1

1171_D2

1172_D1

1172_D2

1173_D1

1173_D2

1174_D1

1174_D2

1175_D1

1175_D2

1176_D1

1176_D2

1178

1177

1179

1180

1181

1183

1184

1185_R

1185_S

1186_R

1186_S

1187_R

1187_S

1188_R

1188_S

1189

1190

1191

1192

1193

1197

1195

1196

1199

1200

1203

1204

1211_CT1

1211_CT2

1217

1219

1221

1223

1225

1226

1227

1229_D1

1229_D2

1237

1239

1243

1245_R

1245_S

1247_R

1247_S

1252

1265

1267

1269

1271

1283

1334

1335

1336

1337

1338

1339

1340

1345

1347

1349

1352

1354_R

1354_S

1355_R

1359

1361

1363

1364

1365

1374_CT1

1374_CT2

1375

1379

1380

1386

1387

1389_D2

1391_D1

1391_D2

1396

1398

1400

1401

1402

1404

1405

1410

1413

1419

1420

1378_CT2

The invention further includes a composition comprising a compound offormula (I), or a salt, solvate, or N-oxide thereof. In one embodiment,the composition is pharmaceutical and further comprises at least onepharmaceutically acceptable carrier.

Preparation of the Compounds of the Invention

Compounds of formula (II) may be prepared by the reaction sequence thatis illustrated in Scheme 1.

The compound of formula (IV) may be reacted with chlorosulfonic acid toyield the sulfonyl chloride of formula (V). The compound of formula (V)may be reacted with a secondary or primary amine of formula HNR⁶R⁶, in asolvent such as but not limited to tetrahydrofuran, dichloromethane,ethyl ether or a mixture thereof, preferably in the presence of atertiary base such as but not limited to triethylamine,diisopropylethylamine or pyridine, to yield the compound of formula(VI), which may be coupled to an amine via an amide bond, yielding thecompound of formula (II). The amide coupling may be performed in thepresence of a coupling agent, such as but not limited to DCC(N,N′-dicyclohexyl carbodiimide), DIC (N,N′-diisopropylcarbodiimide),EDC (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide), HBTU(O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate),HATU (2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate methanaminium), HCTU((2-(6-chloro-1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminiumhexafluorophosphate), TBTU(O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate),or PyBOP (benzotriazol-1-yl-oxytripyrrolidino-phosphoniumhexafluorophosphate), in a solvent such as but not limited totetrahydrofuran, dichloromethane, or a mixture thereof, and in theoptional presence of a tertiary base, such as but not limited totriethylamine, diisopropylethylamine or pyridine. Alternatively, thesulfonyl chloride of formula (V) may be reacted with a chlorinatingreagent, such as but not limited to thionyl chloride, phosgene,diphosgene or triphosgene, to yield the acyl chloride of formula (VII).The compound of formula (VII) may then be reacted with an amine in asolvent such as but not limited to tetrahydrofuran, dichloromethane,ethyl ether or a mixture thereof, under conditions that do not promotethe reaction of the sulfonyl chloride group with the amine, to yield thecompound of formula (VIII), which may then be reacted with the amineHNR⁶R⁶ in a solvent such as but not limited to tetrahydrofuran, toluene,dichloromethane, or a mixture thereof, and in the presence of a tertiarybase, such as but not limited to triethylamine, diisopropylethylamine orpyridine, to yield the compound of formula (II).

Compounds of formula (III) may be prepared by the reaction scheme thatis illustrated in Scheme 2.

The compound of formula (IX) may be reacted with a secondary or primaryamine of formula HNR⁶R⁶, in a solvent such as but not limited totetrahydrofuran, dichloromethane, ethyl ether or a mixture thereof, inthe presence of a coupling agent, such as but not limited to DCC, EDC,HBTU, HATU, HCTU, TBTU, or PyBOP, in a solvent such as but not limitedto tetrahydrofuran, dichloromethane, or a mixture thereof, and in theoptional presence of a tertiary base, such as but not limited totriethylamine, diisopropylethylamine or pyridine, to yield the compoundof formula (X). The compound of formula (X) may be treated with a base,such as but not limited to lithium hydroxide, sodium hydroxide orpotassium hydroxide, to yield the compound of formula (XI). The compoundof formula (XI) may be reacted with a secondary or primary amine, in asolvent such as but not limited to tetrahydrofuran, dichloromethane,ethyl ether or a mixture thereof, in the presence of a coupling agent,such as but not limited to DCC, EDC, HBTU, HATU, HCTU, TBTU, or PyBOP,in a solvent such as but not limited to tetrahydrofuran,dichloromethane, or a mixture thereof, and in the optional presence of atertiary base, such as but not limited to triethylamine,diisopropylethylamine or pyridine, to yield the compound of formula(III).

The compounds of the invention may possess one or more stereocenters,and each stereocenter may exist independently in either the R or Sconfiguration. In one embodiment, compounds described herein are presentin optically active or racemic forms. It is to be understood that thecompounds described herein encompass racemic, optically-active,regioisomeric and stereoisomeric forms, or combinations thereof thatpossess the therapeutically useful properties described herein.

Preparation of optically active forms is achieved in any suitablemanner, including by way of non-limiting example, by resolution of theracemic form with recrystallization techniques, synthesis fromoptically-active starting materials, chiral synthesis, orchromatographic separation using a chiral stationary phase. In oneembodiment, a mixture of one or more isomer is utilized as thetherapeutic compound described herein. In another embodiment, compoundsdescribed herein contain one or more chiral centers. These compounds areprepared by any means, including stereoselective synthesis,enantioselective synthesis and/or separation of a mixture of enantiomersand/or diastereomers. Resolution of compounds and isomers thereof isachieved by any means including, by way of non-limiting example,chemical processes, enzymatic processes, fractional crystallization,distillation, and chromatography.

The methods and formulations described herein include the use ofN-oxides (if appropriate), crystalline forms (also known as polymorphs),solvates, amorphous phases, and/or pharmaceutically acceptable salts ofcompounds having the structure of any compound of the invention, as wellas metabolites and active metabolites of these compounds having the sametype of activity. Solvates include water, ether (e.g., tethrahydrofuran,methyl tert-butyl ether) or alcohol (e.g., ethanol) solvates, acetatesand the like. In one embodiment, the compounds described herein exist insolvated forms with pharmaceutically acceptable solvents such as water,and ethanol. In another embodiment, the compounds described herein existin unsolvated form.

In one embodiment, the compounds of the invention may exist astautomers. All tautomers are included within the scope of the compoundspresented herein.

In one embodiment, compounds described herein are prepared as prodrugs.A “prodrug” refers to an agent that is converted into the parent drug invivo. In one embodiment, upon in vivo administration, a prodrug ischemically converted to the biologically, pharmaceutically ortherapeutically active form of the compound. In another embodiment, apro drug is enzymatically metabolized by one or more steps or processesto the biologically, pharmaceutically or therapeutically active form ofthe compound.

In one embodiment, sites on, for example, the aromatic ring portion ofcompounds of the invention are susceptible to various metabolicreactions. Incorporation of appropriate substituents on the aromaticring structures may reduce, minimize or eliminate this metabolicpathway. In one embodiment, the appropriate substituent to decrease oreliminate the susceptibility of the aromatic ring to metabolic reactionsis, by way of example only, a deuterium, a halogen, or an alkyl group.

Compounds described herein also include isotopically-labeled compoundswherein one or more atoms is replaced by an atom having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number usually found in nature. Examples of isotopes suitablefor inclusion in the compounds described herein include and are notlimited to ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ³⁶Cl, ¹⁸F, ¹²³I, ¹²⁵I, ¹³N, ¹⁵N, ¹⁵O,¹⁷O, ¹⁸O, ³²P, and ³⁵S. In one embodiment, isotopically-labeledcompounds are useful in drug and/or substrate tissue distributionstudies. In another embodiment, substitution with heavier isotopes suchas deuterium affords greater metabolic stability (for example, increasedin vivo half-life or reduced dosage requirements). In yet anotherembodiment, substitution with positron emitting isotopes, such as ¹¹C,¹⁸F, ¹⁵O and ¹³N, is useful in Positron Emission Topography (PET)studies for examining substrate receptor occupancy. Isotopically-labeledcompounds are prepared by any suitable method or by processes using anappropriate isotopically-labeled reagent in place of the non-labeledreagent otherwise employed.

In one embodiment, the compounds described herein are labeled by othermeans, including, but not limited to, the use of chromophores orfluorescent moieties, bioluminescent labels, or chemiluminescent labels.

The compounds described herein, and other related compounds havingdifferent substituents are synthesized using techniques and materialsdescribed herein and as described, for example, in Fieser and Fieser'sReagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons,1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive OrganicTransformations (VCH Publishers Inc., 1989), March, Advanced OrganicChemistry 4^(th) Ed., (Wiley 1992); Carey and Sundberg, Advanced OrganicChemistry 4th Ed., Vols. A and B (Plenum 2000,2001), and Green and Wuts,Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all ofwhich are incorporated by reference for such disclosure). Generalmethods for the preparation of compound as described herein are modifiedby the use of appropriate reagents and conditions, for the introductionof the various moieties found in the formula as provided herein.

Compounds described herein are synthesized using any suitable proceduresstarting from compounds that are available from commercial sources, orare prepared using procedures described herein.

In one embodiment, reactive functional groups, such as hydroxyl, amino,imino, thio or carboxy groups, are protected in order to avoid theirunwanted participation in reactions. Protecting groups are used to blocksome or all of the reactive moieties and prevent such groups fromparticipating in chemical reactions until the protective group isremoved. In another embodiment, each protective group is removable by adifferent means. Protective groups that are cleaved under totallydisparate reaction conditions fulfill the requirement of differentialremoval.

In one embodiment, protective groups are removed by acid, base, reducingconditions (such as, for example, hydrogenolysis), and/or oxidativeconditions. Groups such as trityl, dimethoxytrityl, acetal andt-butyldimethylsilyl are acid labile and are used to protect carboxy andhydroxy reactive moieties in the presence of amino groups protected withCbz groups, which are removable by hydrogenolysis, and Fmoc groups,which are base labile. Carboxylic acid and hydroxy reactive moieties areblocked with base labile groups such as, but not limited to, methyl,ethyl, and acetyl, in the presence of amines that are blocked with acidlabile groups, such as t-butyl carbamate, or with carbamates that areboth acid and base stable but hydrolytically removable.

In one embodiment, carboxylic acid and hydroxy reactive moieties areblocked with hydrolytically removable protective groups such as thebenzyl group, while amine groups capable of hydrogen bonding with acidsare blocked with base labile groups such as Fmoc. Carboxylic acidreactive moieties are protected by conversion to simple ester compoundsas exemplified herein, which include conversion to alkyl esters, or areblocked with oxidatively-removable protective groups such as2,4-dimethoxybenzyl, while co-existing amino groups are blocked withfluoride labile silyl carbamates.

Allyl blocking groups are useful in the presence of acid- andbase-protecting groups since the former are stable and are subsequentlyremoved by metal or pi-acid catalysts. For example, an allyl-blockedcarboxylic acid is deprotected with a palladium-catalyzed reaction inthe presence of acid labile t-butyl carbamate or base-labile acetateamine protecting groups. Yet another form of protecting group is a resinto which a compound or intermediate is attached. As long as the residueis attached to the resin, that functional group is blocked and does notreact. Once released from the resin, the functional group is availableto react.

Typically blocking/protecting groups may be selected from:

Other protecting groups, plus a detailed description of techniquesapplicable to the creation of protecting groups and their removal aredescribed in Greene and Wuts, Protective Groups in Organic Synthesis,3rd Ed., John Wiley & Sons, New York, N.Y., 1999, and Kocienski,Protective Groups, Thieme Verlag, New York, N.Y., 1994, which areincorporated herein by reference for such disclosure.

Assays

HBV Capsid Protein Assembly Testing

The fluorescence quenching in vitro assembly HBV assay was developedaccording to a method described by Zlotnick and coworkers (NatureBiotechnology 2006, 24:358). The assay is based on the observation thatthe C-termini of the HBV core protein cluster together during capsidformation. This assay utilizes a mutant C150 HBV capsid protein whereall wild-type cysteines are mutated to alanines, but a C-terminalcysteine residue is preserved and is labeled with fluorescent BoDIPY-FLdye. HBV C150Bo protein is highly fluorescent, however the fluorescenceis drastically reduced during the capsid assembly process. Thus, theassay measures the ability and potency of test compounds to modulatecapsid assembly by monitoring the fluorescence of the labeled capsidC150Bo protein.

In a typical assay, the mutant HBV C150 protein (amino acids 1-150,C49A, C61A, C107A, 150C) is cloned into a T7 RNA-polymerase basedexpression vector, expressed in E. coli and purified to homogeneity as adimer. The purified HBV core protein is desalted and labeled withBODIPY-FL Dye.

In a non-limiting embodiment, the assembly assay is conducted in 96-wellplate format. The assembly reactions are carried out in 50 mM Hepesbuffer, pH 7.5 and 150 mM NaCl. The compounds are pre-incubated with theHBV CA protein for 15 min, and the assembly reactions are initiated byaddition of NaCl. The reaction is allowed to continue for 1 hour at roomtemperature.

To determine the effect on capsid assembly, each test compound isinitially screened at 4 different concentrations: 10 μM, 3 μM, 1 μM and0.3 μM in duplicates. Primary hits are compounds that show activity inthe assembly assay at 10 uM and a representative group of these activecompounds is shown in Table 1. Identified primary hits are confirmed infollow-up studies as described elsewhere herein. Known modulators of HBVCA assembly, such as HAP-1 and BAY 41-4109, are used as controlcompounds in these experiments and exhibited EC₅₀ values consistent withthe literature. EC₅₀ values for test compounds are determined viaanalysis of the dose-response curve.

HBV Antiviral Testing

Compounds active in the HBV assembly assay are tested for their activityand toxicity in cellular assay. In the first anti-viral assay, theability of compounds to inhibit HBV replication in an HBV-producinghepatoma cell line using the dot-blot method is evaluated.

Briefly, confluent monolayers of HepG2-2.2.15 cells are incubated withcomplete medium containing various concentrations of a test compound.Three days later, the culture medium is replaced with fresh mediumcontaining the appropriately diluted test compound. Six days followingthe initial administration of the test compound, the cell culturesupernatant is collected, and cell lysis is performed. The samples areapplied onto Nylos membranes and DNA is immobilized to the membrane byUV cross-linking. After pre-hybridization, the HBV probe is added andthe hybridization is performed overnight. The membranes are exposed tothe Kodak films; antiviral activity is calculated from the reduction inHBV DNA levels (EC₅₀). The EC₅₀ for antiviral activity is calculatedfrom the dose response curves of active compounds. Assay performanceover time is monitored by the use of the standard positive controlcompounds ETV, BAY 41-4109, and HAP-1.

Compound cytotoxity (TC₅₀) is measured in this same HepG2-2.2.15 cellline using a CellTiter Blue-based cytotoxicity assay employed asrecommended by manufacturer (Promega). To confirm and expand theseresults, a second antiviral assay is carried out on active compoundsusing the stable HBV cell line HepG2.2.15 and measuring anti-HBV potencyby real-time PCR and cytotoxicity by CellTiter Blue. In this assay, 24hours after cell seeding, HepG2-2.2.15 cells are incubated with completemedium containing various concentrations of a test compound with BAY41-4109 and HAP-1 used as positive controls. After three days, theculture medium is replaced with fresh medium containing theappropriately diluted test compound. The cell culture is collected sixdays following the initial administration of the test compound, followedby HBV DNA extraction using QIAamp 96 DNA Blood Kit (Qiagen). Theextracted HBV DNA is diluted and analyzed by Real-Time PCR. A standardcurve is generated by plotting Ct value vs the amount of HBV plasmidstandard. Cytotoxicity is determined similarly to the above describedmethod by applying a dye uptake method (CellTiter Blue kit, Promega).

Prevention of HBV Pre-Genomic RNA (pgRNA) Incorporation.

The anti-viral activity of the compounds of the invention is assessedbased on their ability to suppress both extracellular and intracellularHBV DNA production in two different cell culture models of HBVreplication. To assess if these effects are due to disruption ofintracellular capsid assembly, a particle-gel assay that allowsquantitation of intracellular viral capsids, as well as encapsidatedpre-genomic RNA and DNA, is performed. The assay relies on agarose gelseparation of viral capsid from free capsid/core subunits and viralpg-RNA and DNA.

Methods of Treatment

The invention includes a method of treatment of an HBV infection in anindividual in need thereof, comprising administering to the individual atherapeutically effective amount of a compound of the invention.

The invention also includes a method of reducing viral load associatedwith an HBV infection in an individual in need thereof, comprisingadministering to the individual a therapeutically effective amount of acompound of the invention.

The invention further includes a method of reducing reoccurrence of anHBV infection in an individual in need thereof, comprising administeringto the individual a therapeutically effective amount of a compound ofthe invention.

The invention also includes a method of reducing the physiologicalimpact of an HBV infection in an individual in need thereof, comprisingadministering to the individual a therapeutically effective amount of acompound of the invention.

The invention further includes a method of reducing, slowing, orinhibiting an HBV infection in an individual in need thereof, comprisingadministering to the individual a therapeutically effective amount of acompound of the invention.

The invention also includes a method of inducing remission of hepaticinjury from an HBV infection in an individual in need thereof,comprising administering to the individual a therapeutically effectiveamount of a compound of the invention.

The invention further includes a method of reducing the physiologicalimpact of long-term antiviral therapy for HBV infection in an individualin need thereof, comprising administering to the individual atherapeutically effective amount of a compound of the invention.

The invention also includes a method of eradicating an HBV infection inan individual in need thereof, comprising administering to theindividual a therapeutically effective amount of a compound of theinvention.

The invention further includes a method of prophylactically treating anHBV infection in an individual in need thereof, wherein the individualis afflicted with a latent HBV infection, comprising administering tothe individual a therapeutically effective amount of a compound of theinvention.

In one embodiment, the methods described herein further compriseadministering at least one therapeutic agent selected from the groupconsisting of nucleotide/nucleoside analogs, entry inhibitors, fusioninhibitors, and any combination of these or other antiviral mechanisms.In another embodiment, the compound of the invention and the at leastone additional therapeutic agent are co-formulated. In yet anotherembodiment, the compound of the invention and the at least oneadditional therapeutic agent are co-administered.

In one embodiment, the individual is refractory to other therapeuticclasses of HBV drugs (e.g., HBV polymerase inhibitors, interferons,viral entry inhibitors, viral maturation inhibitors,literature-described capsid assembly modulators, antiviral compounds ofdistinct or unknown mechanism, and the like, or combinations thereof).In another embodiment, the method of the invention reduces viral load inan individual suffering from an HBV infection to a greater extentcompared to the extent that other therapeutic classes of HBV drugsreduce viral load in the individual.

In one embodiment, the method of the invention reduces viral load in anindividual suffering from an HBV infection, thus allowing lower doses orvarying regimens of combination therapies to be used.

In one embodiment, the method of the invention causes a lower incidenceof viral mutation and/or viral resistance compared to other classes ofHBV drugs, thereby allowing for long term therapy and minimizing theneed for changes in treatment regimens.

In one embodiment, the method of the invention increases theseroconversion rate beyond that of current treatment regimens.

In one embodiment, the method of the invention increases and/ornormalizes and/or restores normal health, elicits full recovery ofnormal health, restores life expectancy, and/or resolves the viralinfection in the individual in need thereof.

In one embodiment, the method of the invention eradicates HBV from anindividual infected with HBV, thereby obviating the need for long termand/or life-long treatment, or shortening the duration of treatment,and/or allowing for reduction in dosing of other antiviral agents.

Accordingly, in one embodiment, provided herein is a method of treatingan HBV infection in an individual in need thereof, comprisingadministering to the individual a therapeutically effective amount of acompound of formula I, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound of formulaII, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound of formulaIIa, or a pharmaceutically acceptable salt thereof. In anotherembodiment, provided herein is a method of treating an HBV infection inan individual in need thereof, comprising administering to theindividual a therapeutically effective amount of compound of formulaIIb, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound of formulaIIc, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound of formulaIII, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound of formulaIV, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound of formulaIVa, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound of formulaIVb, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound of formulaIVc, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound of formulaV, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound of formulaVI, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound of formulaVIa, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound of formulaVIb, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound of formulaVII, or a pharmaceutically acceptable salt thereof.

Accordingly, in one embodiment, provided herein is a method of treatingan HBV infection in an individual in need thereof, comprisingadministering to the individual a therapeutically effective amount ofcompound 318.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 890.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 826.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 891.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 903.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 917.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 924.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 922

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 955D1.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 955D2

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 129.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 132.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 142.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 278.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 305.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 318.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 404.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 507.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 531.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 597D1.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 634.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 694.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 754.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 758.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 768.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 803.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 820.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 919.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 824_D1.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 824_D2.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 825_D1.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 825_D2.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 826.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 843.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 851.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1157.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 867_D1.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 867_D2.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 875.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1161.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 901.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 903.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 916.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 960D1.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 960D2.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 953.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 922.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 924.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 927.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 931.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 935.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 942.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 946D1.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 946D2.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 955D1.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 955D2.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 952.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 958.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 964D1.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 964D2.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 976D1.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 988.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1008.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1021.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1022.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1035.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1078D1.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1086.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1091.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1105.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1114.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1126.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1134CT1.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1134CT2.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1149.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1281D1.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1281D2.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1116.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1130.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1135D1.

Combination Therapies

The compounds of the present invention are intended to be useful incombination with one or more additional compounds useful for treatingHBV infection. These additional compounds may comprise compounds of thepresent invention or compounds known to treat, prevent, or reduce thesymptoms or effects of HBV infection. Such compounds include but are notlimited to HBV polymerase inhibitors, interferons, viral entryinhibitors, viral maturation inhibitors, literature-described capsidassembly modulators, and other agents with distinct or unknownmechanisms that affect the HBV life cycle and/or affect the consequencesof HBV infection.

In non-limiting examples, the compounds of the invention may be used incombination with one or more drugs (or a salt, solvate or prodrugthereof) selected from the group consisting of

HBV reverse transcriptase inhibitors, and DNA and RNA polymeraseinhibitors, including but are not limited to: lamivudine (3TC, Zeffix,Heptovir, Epivir, and Epivir-HBV), entecavir (Baraclude, Entavir),adefovir dipivoxil (Hepsara, Preveon, bis-POM PMEA), tenofovirdisoproxil fumarate (Viread, TDF or PMPA);

interferons, including but not limited to interferon alpha (IFN-α),interferon lambda (IFN-λ), and interferon gamma (IFN-γ);

viral entry inhibitors;

viral maturation inhibitors;

literature-described capsid assembly modulators, such as but not limitedto BAY 41-4109;

compounds of distinct or unknown mechanism, such as but not limited toAT-61((E)-N-(1-chloro-3-oxo-1-phenyl-3-(piperidin-1-yl)prop-1-en-2-yl)benzamide),AT-130((E)-N-(1-bromo-1-(2-methoxyphenyl)-3-oxo-3-(piperidin-1-yl)prop-1-en-2-yl)-4-nitrobenzamide),and similar analogs.

In another embodiment, the additional therapeutic agent selected fromimmune modulator or immune stimulator therapies, which includesbiological agents belonging to the interferon class, such as interferonalpha 2a or 2b or modified interferons such as pegylated interferon,alpha 2a, alpha 2b, lamda; or TLR modulators such as TLR-7 agonists orTLR-9 agonists, or antiviral agents that block viral entry or maturationor target the HBV polymerase such as nucleoside or nucleotide ornon-nucleos(t)ide polymerase inhibitors, and agents of distinct orunknown mechanism including agents that disrupt the function of otheressential viral protein(s) or host proteins required for HBV replicationor persistence.

In an embodiment of the combination therapy, the reverse transcriptaseinhibitor and/or DNA and/or RNA polymerase inhibitor Zidovudine,Didanosine, Zalcitabine, ddA, Stavudine, Lamivudine, Abacavir,Emtricitabine, Entecavir, Apricitabine, Atevirapine, ribavirin,acyclovir, famciclovir, valacyclovir, ganciclovir, valganciclovir,Tenofovir, Adefovir, PMPA, cidofovir, Efavirenz, Nevirapine,Delavirdine, or Etravirine.

In another embodiment of the combination therapy, the TLR-7 agonist isselected from the group consisting of SM360320(9-benzyl-8-hydroxy-2-(2-methoxy-ethoxy)adenine) and AZD 8848(methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(4-morpholinyl)propyl]amino}methyl)phenyl]acetate).

A synergistic effect may be calculated, for example, using suitablemethods such as, for example, the Sigmoid-E_(max) equation (Holford &Scheiner, 19981, Clin. Pharmacokinet. 6: 429-453), the equation of Loeweadditivity (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114:313-326) and the median-effect equation (Chou & Talalay, 1984, Adv.Enzyme Regul. 22: 27-55). Each equation referred to above may be appliedto experimental data to generate a corresponding graph to aid inassessing the effects of the drug combination. The corresponding graphsassociated with the equations referred to above are theconcentration-effect curve, isobologram curve and combination indexcurve, respectively.

Administration/Dosage/Formulations

The regimen of administration may affect what constitutes an effectiveamount. The therapeutic formulations may be administered to the patienteither prior to or after the onset of a HBV infection. Further, severaldivided dosages, as well as staggered dosages may be administered dailyor sequentially, or the dose may be continuously infused, or may be abolus injection. Further, the dosages of the therapeutic formulationsmay be proportionally increased or decreased as indicated by theexigencies of the therapeutic or prophylactic situation.

Administration of the compositions of the present invention to apatient, preferably a mammal, more preferably a human, may be carriedout using known procedures, at dosages and for periods of time effectiveto treat HBV infection in the patient. An effective amount of thetherapeutic compound necessary to achieve a therapeutic effect may varyaccording to factors such as the state of the disease or disorder in thepatient; the age, sex, and weight of the patient; and the ability of thetherapeutic compound to treat HBV infection in the patient. Dosageregimens may be adjusted to provide the optimum therapeutic response.For example, several divided doses may be administered daily or the dosemay be proportionally reduced as indicated by the exigencies of thetherapeutic situation. A non-limiting example of an effective dose rangefor a therapeutic compound of the invention is from about 1 and 5,000mg/kg of body weight/per day. One of ordinary skill in the art would beable to study the relevant factors and make the determination regardingthe effective amount of the therapeutic compound without undueexperimentation.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient that is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

In particular, the selected dosage level will depend upon a variety offactors including the activity of the particular compound employed, thetime of administration, the rate of excretion of the compound, theduration of the treatment, other drugs, compounds or materials used incombination with the compound, the age, sex, weight, condition, generalhealth and prior medical history of the patient being treated, and likefactors well, known in the medical arts.

A medical doctor, e.g., physician or veterinarian, having ordinary skillin the art may readily determine and prescribe the effective amount ofthe pharmaceutical composition required. For example, the physician orveterinarian could start doses of the compounds of the inventionemployed in the pharmaceutical composition at levels lower than thatrequired in order to achieve the desired therapeutic effect andgradually increase the dosage until the desired effect is achieved.

In particular embodiments, it is especially advantageous to formulatethe compound in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form as used herein refers tophysically discrete units suited as unitary dosages for the patients tobe treated; each unit containing a predetermined quantity of therapeuticcompound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical vehicle. The dosage unitforms of the invention are dictated by and directly dependent on (a) theunique characteristics of the therapeutic compound and the particulartherapeutic effect to be achieved, and (b) the limitations inherent inthe art of compounding/formulating such a therapeutic compound for thetreatment of HBV infection in a patient.

In one embodiment, the compositions of the invention are formulatedusing one or more pharmaceutically acceptable excipients or carriers. Inone embodiment, the pharmaceutical compositions of the inventioncomprise a therapeutically effective amount of a compound of theinvention and a pharmaceutically acceptable carrier.

The carrier may be a solvent or dispersion medium containing, forexample, water, ethanol, polyol (for example, glycerol, propyleneglycol, and liquid polyethylene glycol, and the like), suitable mixturesthereof, and vegetable oils. The proper fluidity may be maintained, forexample, by the use of a coating such as lecithin, by the maintenance ofthe required particle size in the case of dispersion and by the use ofsurfactants. Prevention of the action of microorganisms may be achievedby various antibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In manycases, it will be preferable to include isotonic agents, for example,sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol,in the composition. Prolonged absorption of the injectable compositionsmay be brought about by including in the composition an agent whichdelays absorption, for example, aluminum monostearate or gelatin. In oneembodiment, the pharmaceutically acceptable carrier is not DMSO alone.

In one embodiment, the compositions of the invention are administered tothe patient in dosages that range from one to five times per day ormore. In another embodiment, the compositions of the invention areadministered to the patient in range of dosages that include, but arenot limited to, once every day, every two, days, every three days toonce a week, and once every two weeks. It will be readily apparent toone skilled in the art that the frequency of administration of thevarious combination compositions of the invention will vary fromindividual to individual depending on many factors including, but notlimited to, age, disease or disorder to be treated, gender, overallhealth, and other factors. Thus, the invention should not be construedto be limited to any particular dosage regime and the precise dosage andcomposition to be administered to any patient will be determined by theattending physical taking all other factors about the patient intoaccount.

Compounds of the invention for administration may be in the range offrom about 1 μg to about 10,000 mg, about 20 μg to about 9,500 mg, about40 μg to about 9,000 mg, about 75 μg to about 8,500 mg, about 150 μg toabout 7,500 mg, about 200 μg to about 7,000 mg, about 3050 μg to about6,000 mg, about 500 μg to about 5,000 mg, about 750 μg to about 4,000mg, about 1 mg to about 3,000 mg, about 10 mg to about 2,500 mg, about20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 30 mg toabout 1,000 mg, about 40 mg to about 900 mg, about 50 mg to about 800mg, about 60 mg to about 750 mg, about 70 mg to about 600 mg, about 80mg to about 500 mg, and any and all whole or partial incrementstherebetween.

In some embodiments, the dose of a compound of the invention is fromabout 1 mg and about 2,500 mg. In some embodiments, a dose of a compoundof the invention used in compositions described herein is less thanabout 10,000 mg, or less than about 8,000 mg, or less than about 6,000mg, or less than about 5,000 mg, or less than about 3,000 mg, or lessthan about 2,000 mg, or less than about 1,000 mg, or less than about 500mg, or less than about 200 mg, or less than about 50 mg. Similarly, insome embodiments, a dose of a second compound (i.e., a drug used fortreating Parkinson's Disease) as described herein is less than about1,000 mg, or less than about 800 mg, or less than about 600 mg, or lessthan about 500 mg, or less than about 400 mg, or less than about 300 mg,or less than about 200 mg, or less than about 100 mg, or less than about50 mg, or less than about 40 mg, or less than about 30 mg, or less thanabout 25 mg, or less than about 20 mg, or less than about 15 mg, or lessthan about 10 mg, or less than about 5 mg, or less than about 2 mg, orless than about 1 mg, or less than about 0.5 mg, and any and all wholeor partial increments thereof.

In one embodiment, the present invention is directed to a packagedpharmaceutical composition comprising a container holding atherapeutically effective amount of a compound of the invention, aloneor in combination with a second pharmaceutical agent; and instructionsfor using the compound to treat, prevent, or reduce one or more symptomsof HBV infection in a patient.

Formulations may be employed in admixtures with conventional excipients,i.e., pharmaceutically acceptable organic or inorganic carriersubstances suitable for oral, parenteral, nasal, intravenous,subcutaneous, enteral, or any other suitable mode of administration,known to the art. The pharmaceutical preparations may be sterilized andif desired mixed with auxiliary agents, e.g., lubricants, preservatives,stabilizers, wetting agents, emulsifiers, salts for influencing osmoticpressure buffers, coloring, flavoring and/or aromatic substances and thelike. They may also be combined where desired with other active agents,e.g., other analgesic agents.

Routes of administration of any of the compositions of the inventioninclude oral, nasal, rectal, intravaginal, parenteral, buccal,sublingual or topical. The compounds for use in the invention may beformulated for administration by any suitable route, such as for oral orparenteral, for example, transdermal, transmucosal (e.g., sublingual,lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- andperivaginally), (intra)nasal and (trans)rectal), intravesical,intrapulmonary, intraduodenal, intragastrical, intrathecal,subcutaneous, intramuscular, intradermal, intra-arterial, intravenous,intrabronchial, inhalation, and topical administration.

Suitable compositions and dosage forms include, for example, tablets,capsules, caplets, pills, gel caps, troches, dispersions, suspensions,solutions, syrups, granules, beads, transdermal patches, gels, powders,pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs,suppositories, liquid sprays for nasal or oral administration, drypowder or aerosolized formulations for inhalation, compositions andformulations for intravesical administration and the like. It should beunderstood that the formulations and compositions that would be usefulin the present invention are not limited to the particular formulationsand compositions that are described herein.

Oral Administration

For oral application, particularly suitable are tablets, dragees,liquids, drops, suppositories, or capsules, caplets and gelcaps. Thecompositions intended for oral use may be prepared according to anymethod known in the art and such compositions may contain one or moreagents selected from the group consisting of inert, non-toxicpharmaceutically excipients that are suitable for the manufacture oftablets. Such excipients include, for example an inert diluent such aslactose; granulating and disintegrating agents such as cornstarch;binding agents such as starch; and lubricating agents such as magnesiumstearate. The tablets may be uncoated or they may be coated by knowntechniques for elegance or to delay the release of the activeingredients. Formulations for oral use may also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertdiluent.

For oral administration, the compounds of the invention may be in theform of tablets or capsules prepared by conventional means withpharmaceutically acceptable excipients such as binding agents (e.g.,polyvinylpyrrolidone, hydroxypropylcellulose orhydroxypropylmethylcellulose); fillers (e.g., cornstarch, lactose,microcrystalline cellulose or calcium phosphate); lubricants (e.g.,magnesium stearate, talc, or silica); disintegrates (e.g., sodium starchglycollate); or wetting agents (e.g., sodium lauryl sulphate). Ifdesired, the tablets may be coated using suitable methods and coatingmaterials such as OPADRY™ film coating systems available from Colorcon,West Point, Pa. (e.g., OPADRY™ OY Type, OYC Type, Organic Enteric OY-PType, Aqueous Enteric OY-A Type, OY-PM Type and OPADRY™ White,32K18400). Liquid preparation for oral administration may be in the formof solutions, syrups or suspensions. The liquid preparations may beprepared by conventional means with pharmaceutically acceptableadditives such as suspending agents (e.g., sorbitol syrup, methylcellulose or hydrogenated edible fats); emulsifying agent (e.g.,lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily estersor ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).

Granulating techniques are well known in the pharmaceutical art formodifying starting powders or other particulate materials of an activeingredient. The powders are typically mixed with a binder material intolarger permanent free-flowing agglomerates or granules referred to as a“granulation.” For example, solvent-using “wet” granulation processesare generally characterized in that the powders are combined with abinder material and moistened with water or an organic solvent underconditions resulting in the formation of a wet granulated mass fromwhich the solvent must then be evaporated.

Melt granulation generally consists in the use of materials that aresolid or semi-solid at room temperature (i.e. having a relatively lowsoftening or melting point range) to promote granulation of powdered orother materials, essentially in the absence of added water or otherliquid solvents. The low melting solids, when heated to a temperature inthe melting point range, liquefy to act as a binder or granulatingmedium. The liquefied solid spreads itself over the surface of powderedmaterials with which it is contacted, and on cooling, forms a solidgranulated mass in which the initial materials are bound together. Theresulting melt granulation may then be provided to a tablet press or beencapsulated for preparing the oral dosage form. Melt granulationimproves the dissolution rate and bioavailability of an active (i.e.drug) by forming a solid dispersion or solid solution.

U.S. Pat. No. 5,169,645 discloses directly compressible wax-containinggranules having improved flow properties. The granules are obtained whenwaxes are admixed in the melt with certain flow improving additives,followed by cooling and granulation of the admixture. In certainembodiments, only the wax itself melts in the melt combination of thewax(es) and additives(s), and in other cases both the wax(es) and theadditives(s) will melt.

The present invention also includes a multi-layer tablet comprising alayer providing for the delayed release of one or more compounds of theinvention, and a further layer providing for the immediate release of amedication for treatment of Parkinson's Disease. Using awax/pH-sensitive polymer mix, a gastric insoluble composition may beobtained in which the active ingredient is entrapped, ensuring itsdelayed release.

Parenteral Administration

For parenteral administration, the compounds of the invention may beformulated for injection or infusion, for example, intravenous,intramuscular or subcutaneous injection or infusion, or foradministration in a bolus dose and/or continuous infusion. Suspensions,solutions or emulsions in an oily or aqueous vehicle, optionallycontaining other formulatory agents such as suspending, stabilizingand/or dispersing agents may be used.

Additional Administration Forms

Additional dosage forms of this invention include dosage forms asdescribed in U.S. Pat. Nos. 6,340,475; 6,488,962; 6,451,808; 5,972,389;5,582,837; and 5,007,790. Additional dosage forms of this invention alsoinclude dosage forms as described in U.S. Patent Applications Nos.20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and20020051820. Additional dosage forms of this invention also includedosage forms as described in PCT Applications Nos. WO 03/35041; WO03/35040; WO 03/35029; WO 03/35177; WO 03/35039; WO 02/96404; WO02/32416; WO 01/97783; WO 01/56544; WO 01/32217; WO 98/55107; WO98/11879; WO 97/47285; WO 93/18755; and WO 90/11757.

Controlled Release Formulations and Drug Delivery Systems

In one embodiment, the formulations of the present invention may be, butare not limited to, short-term, rapid-offset, as well as controlled, forexample, sustained release, delayed release and pulsatile releaseformulations.

The term sustained release is used in its conventional sense to refer toa drug formulation that provides for gradual release of a drug over anextended period of time, and that may, although not necessarily, resultin substantially constant blood levels of a drug over an extended timeperiod. The period of time may be as long as a month or more and shouldbe a release which is longer that the same amount of agent administeredin bolus form.

For sustained release, the compounds may be formulated with a suitablepolymer or hydrophobic material which provides sustained releaseproperties to the compounds. As such, the compounds for use the methodof the invention may be administered in the form of microparticles, forexample, by injection or in the form of wafers or discs by implantation.

In one embodiment of the invention, the compounds of the invention areadministered to a patient, alone or in combination with anotherpharmaceutical agent, using a sustained release formulation.

The term delayed release is used herein in its conventional sense torefer to a drug formulation that provides for an initial release of thedrug after some delay following drug administration and that mat,although not necessarily, includes a delay of from about 10 minutes upto about 12 hours.

The term pulsatile release is used herein in its conventional sense torefer to a drug formulation that provides release of the drug in such away as to produce pulsed plasma profiles of the drug after drugadministration.

The term immediate release is used in its conventional sense to refer toa drug formulation that provides for release of the drug immediatelyafter drug administration.

As used herein, short-term refers to any period of time up to andincluding about 8 hours, about 7 hours, about 6 hours, about 5 hours,about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40minutes, about 20 minutes, or about 10 minutes and any or all whole orpartial increments thereof after drug administration after drugadministration.

As used herein, rapid-offset refers to any period of time up to andincluding about 8 hours, about 7 hours, about 6 hours, about 5 hours,about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40minutes, about 20 minutes, or about 10 minutes, and any and all whole orpartial increments thereof after drug administration.

Dosing

The therapeutically effective amount or dose of a compound of thepresent invention will depend on the age, sex and weight of the patient,the current medical condition of the patient and the progression of HBVinfection in the patient being treated. The skilled artisan will be ableto determine appropriate dosages depending on these and other factors.

A suitable dose of a compound of the present invention may be in therange of from about 0.01 mg to about 5,000 mg per day, such as fromabout 0.1 mg to about 1,000 mg, for example, from about 1 mg to about500 mg, such as about 5 mg to about 250 mg per day. The dose may beadministered in a single dosage or in multiple dosages, for example from1 to 4 or more times per day. When multiple dosages are used, the amountof each dosage may be the same or different. For example, a dose of 1 mgper day may be administered as two 0.5 mg doses, with about a 12-hourinterval between doses.

It is understood that the amount of compound dosed per day may beadministered, in non-limiting examples, every day, every other day,every 2 days, every 3 days, every 4 days, or every 5 days. For example,with every other day administration, a 5 mg per day dose may beinitiated on Monday with a first subsequent 5 mg per day doseadministered on Wednesday, a second subsequent 5 mg per day doseadministered on Friday, and so on.

In the case wherein the patient's status does improve, upon the doctor'sdiscretion the administration of the inhibitor of the invention isoptionally given continuously; alternatively, the dose of drug beingadministered is temporarily reduced or temporarily suspended for acertain length of time (i.e., a “drug holiday”). The length of the drugholiday optionally varies between 2 days and 1 year, including by way ofexample only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days,12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days,120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days,320 days, 350 days, or 365 days. The dose reduction during a drugholiday includes from 10%-100%, including, by way of example only, 10%,15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%,85%, 90%, 95%, or 100%.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, is reduced, as a function of theviral load, to a level at which the improved disease is retained. In oneembodiment, patients require intermittent treatment on a long-term basisupon any recurrence of symptoms and/or infection.

The compounds for use in the method of the invention may be formulatedin unit dosage form. The term “unit dosage form” refers to physicallydiscrete units suitable as unitary dosage for patients undergoingtreatment, with each unit containing a predetermined quantity of activematerial calculated to produce the desired therapeutic effect,optionally in association with a suitable pharmaceutical carrier. Theunit dosage form may be for a single daily dose or one of multiple dailydoses (e.g., about 1 to 4 or more times per day). When multiple dailydoses are used, the unit dosage form may be the same or different foreach dose.

Toxicity and therapeutic efficacy of such therapeutic regimens areoptionally determined in cell cultures or experimental animals,including, but not limited to, the determination of the LD₅₀ (the doselethal to 50% of the population) and the ED₅₀ (the dose therapeuticallyeffective in 50% of the population). The dose ratio between the toxicand therapeutic effects is the therapeutic index, which is expressed asthe ratio between LD₅₀ and ED₅₀. Capsid assembly inhibitors exhibitinghigh therapeutic indices are preferred. The data obtained from cellculture assays and animal studies is optionally used in formulating arange of dosage for use in human. The dosage of such capsid assemblyinhibitors lies preferably within a range of circulating concentrationsthat include the ED₅₀ with minimal toxicity. The dosage optionallyvaries within this range depending upon the dosage form employed and theroute of administration utilized.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, numerous equivalents to thespecific procedures, embodiments, claims, and examples described herein.Such equivalents were considered to be within the scope of thisinvention and covered by the claims appended hereto. For example, itshould be understood, that modifications in reaction conditions,including but not limited to reaction times, reaction size/volume, andexperimental reagents, such as solvents, catalysts, pressures,atmospheric conditions, e.g., nitrogen atmosphere, andreducing/oxidizing agents, with art-recognized alternatives and using nomore than routine experimentation, are within the scope of the presentapplication.

It is to be understood that wherever values and ranges are providedherein, all values and ranges encompassed by these values and ranges,are meant to be encompassed within the scope of the present invention.Moreover, all values that fall within these ranges, as well as the upperor lower limits of a range of values, are also contemplated by thepresent application.

The following examples further illustrate aspects of the presentinvention. However, they are in no way a limitation of the teachings ordisclosure of the present invention as set forth herein.

Examples

The invention is now described with reference to the following Examples.These Examples are provided for the purpose of illustration only, andthe invention is not limited to these Examples, but rather encompassesall variations that are evident as a result of the teachings providedherein.

Materials:

Unless otherwise noted, all starting materials and resins were obtainedfrom commercial suppliers and used without purification.

Library General Design

Region A (Amines and Amino Alcohols):

Region B (Core Variation):

Region C (Anilines, Amines and Aryl Carboxylic Acids):

Part I Intermediate Synthesis (Regions A, B & C)

1 Preparation of Region A Intermediates

1.1 Preparation of A46/47/48

1.1.1 Synthetic Procedure for Preparation 2

To a solution of Compound 1 (5 g, 21.8 mmol) andN,O_Dimethylhydroxylamine (1.6 g, 26.2 mmol) in DCM (50 mL) was addedHATU (9.9 g, 26.2 mmol) and Et₃N (2.65 g, 26.2 mmol) at rt. The formedmixture was stirred at rt overnight. The mixture was washed with water,and purified by column chromatography to give the desired product (3 g,51%).

1.1.2 Preparation of Compound 3

To a solution of Compound 2 (500 mg, 1.84 mmol) in anhydrous THF (5 mL)was added CH₃MgBr (0.8 mL, 2.4 mmol) at 0° C. The formed mixture wasallowed to warm to room temperature. The reaction was quenched withaqueous NH₄Cl solution. The organic layer was separated and extractedwith EtOAc (10 mL×2). The combined organic layers were concentrated togive the crude product, which was purified by column chromatography togive the desired product (300 mg, 72%). ¹H NMR (400 MHz, CDCl₃): δ ppm:4.04 (br, 2H), 2.73 (t, 2H), 2.43 (m, 1H), 2.15 (s, 3H), 1.82 (m, 2H),1.53 (m, 2H), 1.45 (s, 9H).

1.2.3 Preparation of A46

To a solution of Compound 3 (350 mg, 1.54 mmol) in anhydrous DCM (5 mL)was added HCl in dioxane (2 mL) at 0° C. The formed mixture was stirredfor 2 h. The formed mixture was concentrated to give the desired productwhich was used for the next step (260 mg, 100%).

A47/48 were prepared following the similar procedure as A46.

1.2 Preparation of A73-80

2.1 Preparation of Compound 2

To RMgBr (0.5 M, 20 mmol) in THF was added a solution of Compound 1 (2.0g, 10.56 mmol) in THF (20 mL) at 0-4° C. The formed mixture was stirredat rt for 3 h. The reaction was quenched by NH₄Cl solution, and themixture was extracted with EtOAc (20 mL×3). The organic layer wasconcentrated to give the crude product, which was purified by columnchromatography to give the desired product.

2.2 Preparation of Compound 3

To a solution of Compound 2 (10 mmol) in DMF (40 mL) was added NaH (10mmol) at 0° C., After stirring for 30 min, a solution of MeI (10 mmol)in DMF (5 mL) was added dropwise, and stirred at rt for 4 h. The mixturewas poured into water and extracted with EA. The combined organic phasewas washed with brine, dried over Na₂SO₄, and concentrated in vacuo. Theresidue was purified through column chromatography to give the desiredproduct.

2.3 Preparation of A73-80

To a solution of Compound 2 or 3 in MeOH was added Pd(OH)₂/C (100 mg),and the formed mixture was stirred under H₂ at 50 psi overnight. The Pdwas filtered and the filtrate was concentrated to give the desiredproduct.

1.3 Preparation of A81/82

1.3.1 Preparation of Compound 2

To a solution of Compound 1 (1.9 g, 10 mmol) in DMSO (30 mL) was addedMe₃SOI (3.3 g, 15 mmol), followed by NaH (0.6 g, 16 mmol) at 0° C. Theformed mixture was stirred at rt overnight. The mixture was poured intowater and extracted with EA. The combined organic phases were washedwith brine, dried over Na₂SO₄, and concentrated in vacu. The residue waspurified through column chromatography to give the desired product.(0.46 g, 23%). ¹H NMR (400 MHz, CDCl₃): δ: 7.34 (m, 4H), 7.30 (m, 1H),3.55 (s, 2H), 2.62 (s, 2H), 2.55 (m, 4H), 1.83 (m, 2H), 1.52 (m, 2H).

1.3.2 Preparation of Compound 3

A mixture of Compound 2 (3.0 g, 14.76 mmol) in H₂SO₄ (60 mL, 0.2 M) wasstirred at rt overnight. The mixture was neutralized with NaOH solutionto pH8. The formed mixture was extracted with EtOAc. The combinedorganic layers were concentrated to give the desired product (1.5 g,46%). ¹H NMR (400 MHz, CDCl₃): δ ppm: 7.32 (m, 4H), 7.27 (m, 1H), 3.52(s, 2H), 3.44 (s, 2H), 2.64 (m, 2H), 2.36 (m, 2H), 2.03 (m, 2H), 1.59(m, 4H).

1.3.3 Preparation of A81

To a solution of Compound 3 (500 mg, 2 mmol) in CH₃OH (5 mL) was addedPd(OH)₂/C (50 mg). The formed mixture was hydrogenated overnight underH₂ atmosphere. The catalyst was filtered and the filtrate wasconcentrated to give the desired product (200 mg, 68%).

1.3.4 Preparation of Compound 4

To a solution of A11 (100 mg, 0.762 mmol) and Et₃N (116 mg, 1.14 mmol)in MeOH (3 mL) was added Boc₂O (200 mg, 0.915 mmol) at rt. The formedmixture was stirred overnight. The mixture was concentrated and dilutedwith DCM (20 ml). The resulting mixture was washed with water. Theorganic layer was concentrated to give the crude product which was usedfor the next step (180 mg, 68%).

1.3.5 Preparation of compound 5

To a suspension of NaH (125 mg, 3.11 mmol) in THF (3 mL) was added asolution of compound 4 (240 mg, 1.04 mmol) at rt. The formed mixture wasstirred for 10 minutes. Then CH₃I (736 mg, 5.19 mmol) was added to theabove mixture. The mixture was stirred overnight. The reaction wasquenched by water, and the formed mixture was concentrated to give thecrude product, which was purified by column chromatography to give thedesired product (200 mg, 74%). ¹H NMR (400 MHz, CDCl₃): δ ppm: 3.72 (m,2H), 3.35 (s, 3H), 3.29 (s, 2H), 3.24 (s, 3H), 3.06 (m, 2H), 1.74 (m,2H), 1.47 (m, 1H), 1.46 (s, 9H), 1.42 (m, 1H).

1.3.6 Preparation of A82

Compound 5 (200 mg, 0.77 mmol) was treated with 4 N HCl in methanol (10mL), and stirred at rt for 20 min. The mixture was concentrated in vacuoto give a HCl salt (150 mg, 99%).

1.4 Preparation of A67-72

1.4.1 Preparation of Compound 2

LDA (4 mmol) was added to a solution of dry THF (20 mL) slowly at −30°C. The solution was chilled to −75° C. and then Compound 1 (1.00 g, 3.89mmol) in THF (10 mL) was added dropwise. After addition, the reactionmixture was stirred for 1 h at −30° C. RX (5 mmol) in THF (10 mL) wasadded dropwise. The resulted mixture was stirred at RT overnight.Aqueous NH₄Cl (30 mL) was added and the aqueous layer was extracted withethyl acetate (20 mL 3). The organic layer was dried and concentrated togive the crude product, which was purified by column on silica gel togive the product.

1.4.2 Preparation of Compound 3

Compound 2 (4.87 mmol) was dissolved in HCl/dioxane (20 mL). The mixturewas stirred at RT for 2 h. The solvent was removed to give the product.

1.4.3 Preparation of A67/68/69

LiAlH₄ (367.80 mg, 9.93 mmol) was suspended in dry THF (30 mL) at 0.Compound 3 (4.96 mmol) in dry THF (10 mL) was added slowly. The reactionmixture was stirred at RT overnight. The reaction mixture was quenchedwith water (0.37 mL) and 10% NaOH (0.37 mL), then water (1.11 mL) wasadded. The mixture was stirred at RT for 30 min and filtered. Thefiltrate was concentrated to give the product.

1.4.4 Preparation of Compound 4

To a mixture of TEA (6 mmol) and Boc₂O (5 mmol) in DCM (40 mL) was addedA14/15/16 (4.2 mmol), and stirred at rt overnight. The mixture waswashed with 1N HCl, NaHCO3 and brine, dried over Na₂SO₄, andconcentrated in vacuo. The residue was purified through columnchromatography to give the desired product.

1.4.5 Preparation of Compound 5

NaH (13 mmol) was suspended in dry THF (10 mL) and cooled to 0° C. Asolution of compound 4 (6.55 mmol) in dry THF (10 mL) was added slowly.The reaction mixture was stirred at Or for 20 min and then MeI (1.4 g,9.8 mmol) was added dropwise. The resulted mixture was stirred at RTovernight. The reaction mixture was washed with water and concentrated.The residue was purified through column chromatography to give thedesired product.

1.4.6 Preparation of A70/71/72

Compound 5 (3.4 mmol) was dissolved in HCl/dioxane (20 mL). The mixturewas stirred at RT for 2 h. The solvent was removed to give the product.

1.5 Preparation of A84-89

1.5.1 Preparation of Compound 2

To a solution of compound 1 (2.0 g, 7.37 mmol) and K₂CO₃ (3.06 g, 22.11mmol) in acetone (80 mL) was added RX (2.30 g, 14.74 mmol) slowly at RT.The reaction mixture was stirred under reflux overnight. The reactionmixture was filtered and concentrated. The residue was dissolved inwater (50 mL) and extracted with ethyl acetate (50 mL2). The organiclayer was dried and concentrated to give the product.

1.5.2 Preparation of Compound 3

Compound 2 (13.36 mmol) was dissolved in 20% HCl (50 mL). The reactionmixture was stirred under reflux for 2 days. The solvent was removed andthe crude product was dissolved in THF (100 mL) and H₂O (20 mL). Boc₂O(5.83 g, 26.73 mmol) and Na₂CO₃ (4.25 g, 40.10 mmol) was added. Thereaction mixture was stirred at RT overnight. The crude product waspurified by column to give the product.

1.5.3 Preparation of Compound 4

To a solution of compound 3 (11.00 mmol) in ethanol (50 mL) was addedKBH₄ (0.712 g, 13.20 mmol) slowly at 0° C. The reaction mixture wasstirred at 0° C. for 0.5 h and the stirred at RT for 2 h. The reactionmixture was pure into water (50 mL) and extracted with DCM (50 mL3). Theorganic layer was dried and concentrated to give the product.

1.5.4 Preparation of A84/85/86

Compound 4 (4.36 mmol) was dissolved in HCl/dioxane (20 mL). The mixturewas stirred at RT for 2 h. The solvent was removed to give the product.

1.5.5 Preparation of Compound 5

To a solution of Compound 4 (17 mmol) in dry THF (10 mL) was added NaH(20 mmol) at 0° C. slowly. The reaction mixture was stirred at 0° C.slowly, then MeI (20 mmol) was added dropwise. The resulted mixture wasstirred at RT overnight. The reaction mixture was washed with water andconcentrated. Purification by chromatograph gave the product.

1.5.4 Preparation of A87/88/89

Compound 5 (5.5 mmol) was dissolved in HCl/dioxane (25 mL). The mixturewas stirred at RT for 2 h. The solvent was removed to give the product.

1.6 Preparation of A103/104

1.6.1 Preparation of Compound 2

To a solution of compound 1 (1.9 mmol) was added NaOH (1.9 mmol) in MeOH(20 ml), and stirred at rt for 30 min NaBH4 (14.4 mmol) was added inportions, and the mixture was stirred at rt overnight. Water was addedslowly, and stirred at rt for 30 min. The mixture was extracted with EA.The combined organic phase was washed with brine, dried over Na₂SO₄, andconcentrated in vacuo. The residue was purified through columnchromatography to give the desired product.

1.6.2 Preparation of A104

To a solution of compound 2 (450 mg, 2 mmol) in MeOH (50 mL) was addedPd(OH)₂/C (100 mg), and the formed mixture was stirred under H₂ at 50psi overnight. The catalyst was filtered and the filtrate wasconcentrated to give the desired product (230 mg, 88%).

A103 was prepared following the same procedure with A104.

1.7 Preparation of A90191192

1.7.1 Preparation of Compound 2

A solution of ethyl acetate (2.11 g, 24 mmol) in THF (30 mL) was addedto lithium diisopropylamide solution (13 mL, 2.0 M in THF, 26 mmol) at−78° C. After stirring at the same temperature for 30 min, a solution ofCompound 1 (3.8 g, 20 mmol) in THF (30 mL) was added and the mixture wasstirred for 15 h at −40° C. The reaction solution was quenched withsaturated NH₄Cl (100 mL) and extracted with ethyl acetate (250 mL 2).The combined organic layers were dried (Na₂SO₄) and concentrated invacuum. Column chromatography of the residue, using petroleumether/ethyl acetate (2:1) as eluent, gave Compound 2 as white solid.(4.2 g, yield: 80%).

1.7.2 Preparation of Compound 3

Compound 2 (2.63 g, 10 mmol) was dissolved in THF (40 mL), then LiAlH₄(380 mg, 10 mmol) was added, the mixture was stirred at rt for 1 h.Water (0.4 g) was added, then NaOH (0.4 mL, 10%) was added, the mixturewas stirred for 30 min, water (1.2 mL) was added, the solid wasfiltered, the filtrate was concentrated and extracted with EtOAc (100mL), the organic layer was concentrated to give desired Compound 3 (2.1g, yield: 90%)

1.7.3 Preparation of A90

To a solution of compound 3 (460 mg, 2 mmol) in CH₃OH (5 mL) was addedPd(OH)₂/C (50 mg). The formed mixture was hydrogenated overnight underH₂ atmosphere. The catalyst was filtered and the filtrate wasconcentrated to give the desired product A90 (190 mg, 68%).

1.7.4 Preparation of Compound 4

A90 (1.45 g, 10 mmol) was dissolved in MeOH (20 mL), then Boc₂O (2.16 g,10 mmol) and TEA (1.5 g, 15 mmol) was added. The mixture was stirred atrt for 3 h. The solution was concentrated and dissolved with EA, washedwith 1N HCl and NaHCO3, concentrated in vacuo to give desired compound 2(2.3 g, yield: 100%).

1.7.5 Preparation of Compound 5

To a suspension of NaH (240 mg, 6 mmol) in THF (10 mL) was added asolution of Compound 4 (490 mg, 2 mmol) at rt. The formed mixture wasstirred for 10 minutes. Then CH₃I (852 mg, 6 mmol) was added to theabove mixture. The mixture was stirred overnight. The reaction wasquenched by water, and the formed mixture was concentrated to give thecrude product, which was purified by column chromatography(PE:EtOAc=10:1) to give the desired product (437 mg, 80%).

1.7.6 Preparation of A92

Compound 5 (2.73 g, 10 mmol) was dissolved in DCM (20 mL), Then CF₃COOH(20 mL) was added, the mixture stirred at room temperature for 2 hours.The solution was concentrated to give desired A92 (1.6 g, 91%).

1.7.7 Preparation of Compound 2:

To a solution of Compound 6 (2.4 g, 10 mmol) in DMF (30 mL) was addedTEA (2.02 g, 20 mmol) and TBSCl (1.5 g, 10 mmol) at rt. The formedmixture was stirred for 12 hours. The reaction was quenched by water(100 mL), and extracted by EtOAc (100 mL). The organic layer wasconcentrated to give the crude product, which was purified by columnchromatography (PE:EtOAc=10:1) to give the desired product (2.0 g, 80%).

1.7.8 Preparation of Compound 8

To a solution of compound 7 (700 mg, 2 mmol) in CH₃OH (5 mL) was addedPd(OH)₂/C (250 mg) and Boc₂O (512 mg, 2 mmol). The formed mixture washydrogenated overnight under H₂ atmosphere. The catalyst was filteredand the filtrate was concentrated to give the desired product 4 (575 mg,81%).

1.7.9 Preparation of Compound 9

To a suspension of NaH (240 mg, 6 mmol) in THF (10 mL) was added asolution of compound 8 (720 mg, 2 mmol) at rt. The formed mixture wasstirred for 10 minutes. Then CH₃I (852 mg, 6 mmol) was added to theabove mixture. The mixture was stirred overnight. The reaction wasquenched by water, and the formed mixture was concentrated to give thecrude product, which was purified by column chromatography(PE:EtOAc=10:1) to give the desired product 9 (520 mg, 69%).

1.7.10 Preparation of A91

Compound 9 (373 mg, 1 mmol) was dissolved in DCM (5 mL), Then CF₃COOH (5mL) was added, the mixture stirred at room temperature for 2 hours. Thesolution was concentrated to give desired compound A91 (273 mg, 100%).1.8 Preparation of A93/94

1.8.1 Preparation of Compound 2

To a solution of (Diethoxy-phosphoryl)-acetic acid ethyl ester (4.5 g,20 mmol) in THF (50 mL) was added NaH (960 mg, 24 mmol) at 0° C. Theformed mixture was stirred for 10 minutes. Then Compound 1 (4.1 g, 20mmol) was added to the above mixture. The mixture was stirred overnight.The reaction was quenched by water, and the formed mixture was extractedwith EtOAc (200 mL). The organic layer was concentrated to give thecrude product, which was purified by column chromatography(PE:EtOAc=5:1) to give the desired product 2 (3.36 g, 71%).

1.8.2 Preparation of Compound 3

Compound 2 (2.59 g, 10 mmol) was dissolved in THF (40 mL), then LiAlH₄(380 mg, 10 mmol) was added, the mixture was stirred at room temperaturefor 1 hour. Water (0.4 g) was added, then NaOH (0.4 mL, 10%) was added,the mixture was stirred for 30 min, water (1.2 mL) was added, the solidwas filtered, the filtrate was concentrated and extracted with EtOAc(100 mL), the organic layer was concentrated to give desired compound 5(2.07 g, yield: 90%).

1.8.3 Preparation of A93

To a solution of Compound 3 (2.31 g, 10 mmol) in CH₃OH (30 mL) was addedPd/C (1.0 g). The formed mixture was hydrogenated overnight under H₂atmosphere. The catalyst was filtered and the filtrate was concentratedto give the desired product A93 (1.28 g, 90%).

1.8.4 Preparation of Compound 4

A93 (1.43 g, 10 mmol) was dissolved in MeOH (20 mL), then Boc₂O (2.16 g,10 mmol) and TEA (1.5 g, 15 mmol) was added. The mixture was stirred atroom temperature for 3 hours. The solution was concentrated in vacuo.The residue was dissolved with EA, washed with 1N HCl and saturatedNaHCO₃, dried over Na₂SO₄ and concentrated in vacuo to give desiredCompound 4 (2.43 g, yield: 100%).

1.8.5 Preparation of Compound 5

To a suspension of NaH (1.2 g, 30 mmol) in THF (50 mL) was added asolution of Compound 4 (2.43 g, 10 mmol) at rt. The formed mixture wasstirred for 10 minutes. Then CH₃I (4.2 g, 30 mmol) was added to theabove mixture. The mixture was stirred overnight. The reaction wasquenched by water, and the formed mixture was concentrated to give thecrude product, which was purified by column chromatography(PE:EtOAc=10:1) to give the desired product (2.05 g, 80%).

1.8.6 Preparation of A94

Compound 5 (2.57 g, 10 mmol) was dissolved in DCM (20 mL), Then CF₃COOH(20 mL) was added, the mixture stirred at room temperature for 2 hours.The solution was concentrated in vauco to give desired A94 (1.57 g,100%).

1.9 Preparation of A95/96

1.9.1 Preparation of Compound 2

To a solution of Compound 1 (10.9 g, 100 mmol) in THF (100 mL) was addedCbzCl (17.6 g, 100 mmol), at 0° C. The formed mixture was stirred for 10minutes. Then CH₃MgBr (100 mL, 100 mmol) was added to the above mixture.The mixture was stirred overnight. The reaction was quenched by water,and the formed mixture was extracted with EtOAc (200 mL). The organiclayer was concentrated to give the crude product, which was purified bycolumn chromatography (PE:EtOAc=4:1) to give the desired product 2 (14.7mg, 58%).

1.9.2 Preparation of Compound 3

To a suspension of Zn (6.5 g, 100 mmol) in AcOH (50 mL) was added asolution of compound 2 (4.9 g, 20 mmol) at rt. The mixture was stirredovernight. The reaction was filtered and concentrated to give the crudeproduct, which was purified by column chromatography (PE:EtOAc=5:1) togive the desired product 3 (2.9 g, 62%).

1.9.3 Preparation of Compound 4

To a solution of (Diethoxy-phosphoryl)-acetic acid ethyl ester (4.5 g,20 mmol) in THF (50 mL) was added NaH (960 mg, 24 mmol) at 0° C. Theformed mixture was stirred for 10 minutes. Then Compound 3 (4.94 g, 20mmol) was added to the above mixture. The mixture was stirred overnight.The reaction was quenched by water, and the formed mixture was extractedwith EtOAc (200 mL). The organic layer was concentrated to give thecrude product, which was purified by column chromatography(PE:EtOAc=5:1) to give the desired product 4 (3.94 g, 62%).

1.9.4 Preparation of Compound 5

Compound 4 (3.17 g, 10 mmol) was dissolved in THF (40 mL), then LiAlH₄(380 mg, 10 mmol) was added, the mixture was stirred at room temperaturefor 1 hour. Water (0.4 g) was added, then NaOH (0.4 mL, 10%) was added,the mixture was stirred for 30 min, water (1.2 mL) was added, the solidwas filtered, the filtrate was concentrated and extracted with EtOAc(100 mL), the organic layer was concentrated to give desired Compound 5(2.47 g, yield: 90%).

1.9.5 Preparation of A95

To a solution of Compound 5 (2.75 g, 10 mmol) in CH₃OH (30 mL) was addedPd/C (1.0 g). The formed mixture was hydrogenated overnight under H₂atmosphere. The catalyst was filtered and the filtrate was concentratedto give the desired product A33 (1.28 g, 90%).

1.9.6 Preparation of Compound 6

To a solution of Compound 5 (2.31 g, 10 mmol) in CH₃OH (30 mL) was addedPd/C (1.0 g). The formed mixture was hydrogenated overnight under H₂atmosphere. The catalyst was filtered and the filtrate was concentratedto give the desired product (1.28 g, 90%).

1.9.7 Preparation of Compound 7

Compound 6 (1.43 g, 10 mmol) was dissolved in MeOH (20 mL), then Boc₂O(2.16 g, 10 mmol) and TEA (1.5 g, 15 mmol) was added. The mixture wasstirred at room temperature for 3 hours. The solution was concentratedin vacuo, dissolved with EA, washed with 1N HCl and NaHCO3, dried overNa₂SO₄, and concentrated in vacuo to give desired Compound 7 (2.43 g,yield: 100%).

1.9.8 Preparation of Compound 8

To a suspension of NaH (1.2 g, 30 mmol) in THF (50 mL) was added asolution of Compound 7 (2.43 g, 10 mmol) at rt. The formed mixture wasstirred for 10 minutes. Then CH₃I (4.2 g, 30 mmol) was added to theabove mixture. The mixture was stirred overnight. The reaction wasquenched by water, and the formed mixture was concentrated to give thecrude product, which was purified by column chromatography(PE:EtOAc=10:1) to give the desired product (2.05 g, 80%).

1.9.9 Preparation of A96

Compound 8 (2.57 g, 10 mmol) was dissolved in DCM (20 mL), Then CF₃COOH(20 mL) was added, the mixture stirred at room temperature for 2 hours.The solution was concentrated to give desired compound H (1.57 g, 100%).

1.10 Preparation of A53/58

A mixture of compound 1 (1.2 g, 20 mmol) and MeNH2 in THF was heated to70° C. in a sealed tube overnight. The mixture was concentrated invacuo. The residue was re-dissolved in toluene, and concentrated invacuo to give the desired product A53 (1.8 g, 98%). ¹H NMR (400 MHz,CDCl₃): δ ppm: 3.79-3.84 (m, 1H), 2.42-2.46 (m, 2H), 3.35 (s, 3H), 1.16(d, 2H).

A58 was prepared following the same procedure as A53.

1.11 Preparation of A98

1.11.1 Preparation of Compound 3

To a solution of compound 2 (10 mL, 1 M, 10 mmol) in THF was added asolution of Compound 1 (0.95 g, 5 mmol) in THF (20 mL) at 0° C. Theformed mixture was stirred at rt for 3 h. The reaction was quenched byNH₄Cl solution, and the mixture was extracted with EtOAc (20 mL×3). Theorganic layer was concentrated to give the crude product, which waspurified by column chromatography to give the desired product (1.1 g,78%). LCMS: 286.3 [M+1].

1.11.2 Preparation of A98

To a solution of Compound 3 (1.1 g, 3.8 mmol) in MeOH was addedPd(OH)₂/C (100 mg), and the formed mixture was stirred under H₂ balloonovernight. The Pd was filtered and the filtrate was concentrated to givethe desired product (680 mg, 90%). ¹H NMR (400 MHz, CDCl₃): δ ppm:7.24-7.38 (m, 3H), 6.95-7.00 (m, 1H), 3.10-3.17 (m, 2H), 2.98-3.01 (m,2H), 1.99-2.06 (m, 2H), 1.72-1.79 (m, 2H).

1.12 Preparation of A971991101

1.12.1 Preparation of Compound 2

To a solution of 1-bromo-4-fluorobenzene (1.75 g, 10 mmol) in THF wasadded n-BuLi (4 mL, 10 mmmol, 2.5 M) at −78 under N2. After stifling for15 min, a solution of Compound 1 (0.95 g, 5 mmol) in THF (20 mL) wasadded dropwise at −78° C. The formed mixture was stirred at rt for 3 h.The reaction was quenched by NH₄Cl solution, and the mixture wasextracted with EtOAc (20 mL×3). The organic layer was concentrated togive the crude product, which was purified by column chromatography togive the desired product (0.9 g, 64%). LCMS: 286.3 [M+1].

1.12.2 Preparation of A97

To a solution of Compound 2 (0.9 g, 3.1 mmol) in MeOH was addedPd(OH)₂/C (100 mg), and the formed mixture was stirred under H₂ balloonovernight. The Pd was filtered and the filtrate was concentrated to givethe desired product (0.5 g, 82%). LCMS: 196.2 [M+1].

A99/101 were prepared following the same procedure as A97.

1.13 Preparation of A100/102

1.12.1 Preparation of Compound 2

To a solution of 4-bromo-1,2-difluorobenzene (3.86 g, 20 mmol) in THF(50 mL) was added I₂ (64 mg, 0.25 mmol), followed by Mg (0.48 g, 20mmol) at rt under N2. After stirring for 1 h, the Mg was disappeared, asolution of Compound 1 (1.9 g, 10 mmol) in THF (20 mL) was addeddropwise at 0° C. The formed mixture was stirred at rt for 3 h. Thereaction was quenched by NH₄Cl solution, and the mixture was extractedwith EtOAc (500 mL×3). The organic layer was concentrated to give thecrude product, which was purified by column chromatography to give thedesired product (2.8 g, 93%). LCMS: 304.1 [M+1].

1.12.2 Preparation of A100

To a solution of Compound 2 (2.8 g, 9.3 mmol) in MeOH (200 mL) was addedPd(OH)₂/C (0.5 g), and the formed mixture was stirred under H₂ balloonovernight. The Pd was filtered and the filtrate was concentrated to givethe desired product (1.6 g, 80%). LCMS: 214.1 [M+1].

A102 was prepared following the same procedure as A100.

1.14 Preparation of A114

1.14.1 Preparation of Compound 2

To a slurry of Compound 1 (6.5 g, 79 mmol) and Compound 2 (10.2 g, 69mmol) in MeOH (100 mL) was added a aqueous Na2CO3 (6 mL, 2 N, 12 mmol),and stirred at rt for 24 h. The solid was collected by filteration,washed with MeoH and dried in vacuo, which was used in the next step (14g, crude). LCMS: 230.2 [M+1].

1.14.1 Preparation of Compound 4

To a mixture of Compound 3 (14 g, 61 mmol) in MeOH/THF (300 mL/50 mL)was added NaBH4 (3.4 g, 90 mmol) at 0° C., and stirred at rt overnight.1 N HCl was added slowly to quenched the reaction. The mixture wasconcentrated in vacuo, and the mixture was extracted with EtOAc (500mL×3). The organic layer was concentrated to give the crude product,which was purified by column chromatography to give the compound 4 (8.0g, 57%). LCMS: 236.1 [M+1].

1.14.3 Preparation of A114

A mixture of compound 4 (8.0 g, 34 mmol) in MeOH (100 mL) was addedconcentrated HCl (10 mL), and heated to reflux for 2 h. The mixture wasconcentrated in vacuo. The residue was dissolved with water and washedwith EA. The aqueous phase was concentrated in vacuo to give the desiredproduct with HCl salt (2.8 g, 82%). ¹H NMR (400 MHz, CDCl₃): δ ppm: 4.33(bs, 1H), 3.66 (bs, 1H), 2.08-2.16 (m, 2H), 1.74-1.90 (m, 4H).

1.15 Preparation of A113

A mixture of Compound 1 (4.2 g, 50 mmol) and ammonia (25%, 20 mL) inMeOH (100 mL) was heated to 60° C. in a sealed tube overnight. Themixture was concentrated in vacuo. The residue was dissolved with 0.5 NHCl (20 mL) and washed with EA. The aqueous phase was concentrated invacuo to give the desired product A44, which was used in the next stepdirectly (3.0 g, 59%).

1.16 Preparation of A121

1.16.1 Preparation of Compound 2

To MeMgBr (3 mL, 12 mmol) in THF was added dropwise a solution ofCompound 1 (1.0 g, 4.7 mmol) in THF (20 mL) at 0-4° C. The formedmixture was stirred at rt for 3 h. The reaction was quenched by NH₄Clsolution, and the mixture was extracted with EtOAc (20 mL×3). Theorganic layer was concentrated to give the desired product 2, useddirectly in the next step without further purification (0.97 g, 94%).

1.16.2 Preparation of A121

To a solution of Compound 2 (970 mg, 4.43 mmol) in DCM (10 mL) was addedTFA (5 mL). The formed mixture was stirred overnight at rt. The reactionmixture was concentrated to give the product A121 (1.3 g), which wasused in the next step directly.

1.17 Preparation of A125

1.17.1 Preparation of Compound 2

To a solution of Compound 1 (8.2 g, 0.1 mol) and NBS (21.4 g, 0.12 mol)in CCl₄ (100 mL), was added AIBN (3.3 g, 20 mmol) at rt, and heated toreflux for 3 h. The mixture was washed with Na₂SO₃, sat. NaHCO₃ andbrine, dried over Na₂SO₄, and concentrated to afford desired product 2(8.5 g, 53%), used in the next step directly.

1.17.2 Preparation of Compound 3

To a solution of Compound 2 (4.0 g, 24.8 mmol) and phenylmethanamine(3.2 g, 29.8 mmol) in anhydrous THF (60 mL), was added K₂CO₃ (5.1 g,37.2 mmol), and heated to 60° C. for 5 h. After cooling to rt, themixture was diluted with EA, and H₂O (80 mL). The aqueous phase wasextracted with EA (100 mL3). The combined organic phase was washed withbrine, dried over Na₂SO₄, concentrated to afford crude product which waspurified by silica gel column chromatography (20-50% EtOAc in PE) toafford 3 (3.1 g, 68 yield). LCMS: 187 [M+1].

1.17.3 Preparation of Compound 4

Compound 3 (1.0 g, 5.3 mmol) was dissolved in DCM (20 mL), CF₃COOH (3.0g, 26.7 mmol) was added and stirred for 30 minutes at rt. m-CPBA (1.5 g,8.6 mmol) was added and the mixture stirred at rt overnight. AqueousNaHCO₃ was added to the reaction mixture and the phases separated andextracted with DCM (3.50 mL). The combined organic extracts were dried,filtered and concentrated in vacuo to yield the crude amino diol.Purification by chromatography on SiO₂ (EA) gave 4 (600 mg, 51%) as acolourless oil. LCMS: 222 [M+1].

1.17.4 Preparation of A125

To a solution of compound 5 (600 mg, 2.7 mmol) in CH₃OH (8 mL) was addedPd(OH)₂/C (60 mg). The formed mixture was hydrogenated overnight underH₂ atmosphere. The catalyst was filtered and the filtrate wasconcentrated to give the desired product (340 mg, 95%).

1.18 Preparation of A127

1.18.1 Preparation of Compound 2

To a solution of compound 1 (7.0 g, 25.8 mmol) in EtOH (100 mL) wasadded NaBH4 (9.8 g, 258 mmol) in portions at 0° C. The reaction mixturewas stirred at 0 for 0.5 h and then stirred at RT overnight. Thereaction mixture was poured into water (100 mL) and extracted with DCM(100 mL3). The organic layer was dried and concentrated to give theproduct 2 (4.5 g, 75%).

1.18.3 Preparation of Compound 3

To a solution of Compound 2 (2.5 g, 10.8 mmol) and imidazole (0.9 g, 12mmol) in anhydrous DCM (30 mL), TBSCl (1.7 g, 11.4 mmol) was addeddropwise at 0° C. After complete addition, the solution was allowed towarm to rt, and stirred for 2 h. The reaction mixture was dissolved withDCM, washed with 1N HCl, saturated NaH CO3 and brine, dried over Na₂SO₄,and concentrated to afford desired product 3 (3.3 g, 89%). LCMS: 345[M+1].

1.18.4 Preparation of Compound 4

To a solution of Compound 3 (3.3 g, 9.6 mmol) and TEA (1.16 g, 11.5mmol) in anhydrous THF (30 mL), AcCl (0.83 g, 11.6 mmol) was addeddropwise at 0° C. After complete addition, the solution was allowed towarm to rt, and stirred for 2 h. The reaction mixture was dissolved withDCM, washed with 1N HCl, saturated Na2 CO3 and brine, dried over Na₂SO₄,and concentrated to afford desired product 4 (3.5 g, 95%). LCMS: 388[M+1]

1.18.5 Preparation of Compound 5

To a solution of compound 4 (3.5 g, 9.0 mmol) in THF (40 mL) was addedTBAF (2.75 g, 10 mmol). The formed mixture was stirred at rt overnight.The mixture was poured into water and extracted with EA. The combinedorganic phase was washed with 1N HCl, saturated NaHCO3 and brine, driedover Na₂SO₄, and concentrated in vacuo. The residue was purified throughcolumn chromatography to give the desired product 5. (2.4 g, 96%).

1.18.6 Preparation of Compound 6

To a solution of Compound 5 (1.0 g, 3.7 mmol) in anhydrous DCM (15 mL),DAST (1.19 g, 7.4 mmol, 2.0 eq) was added dropwise at −78° C. under N₂.After addition the solution was warmed to rt gradually and stirred for 2h. Quenched the reaction with sat. NaHCO₃ (30 mL), extracted with DCM(30 mL3), combined the organic layer, washed with brine, dried overNa₂SO₄, and concentrated to afford desired product 6 (870 mg, 87%).

1.18.7 Preparation of Compound 7

To a solution of Compound 6 (870 mg, 3.2 mmol) and NaOH (256 mg, 6.4mmol) in MeOH/H₂O (10 mL, v:v=4:1). The formed mixture was stirredovernight at rt. The reaction mixture was neutralized with 1N HClsolution and concentrated to give the crude product (720 mg, 96%).

1.18.7 Preparation of A127

To a solution of Compound 7 (720 mg, 3.1 mmol) in DCM (6 mL) was addedTFA (5 mL). The formed mixture was stirred overnight at rt. The reactionmixture was concentrated to give the crude product (800 mg, crude), usedin the next step directly.

1.19 Preparation of A119

1.19.1 Preparation of Compound 2

To a solution of compound 1 (4.0 g, 21.6 mmol) in ethanol (40 mL) wasadded NaBH₄ (1.64 g, 43.2 mmol) slowly at 0. The reaction mixture wasstirred at RT for 5 h. The reaction mixture was quenched with NH₄Cl (50mL) and extracted with ethyl acetate (50 mL3). The organic layer wasdried and concentrated to give the product.

1.19.2 Preparation of A119

Compound 2 (4 g 21.6 mmol) was dissolved in HCl/EA (25 mL). The mixturewas stirred at RT for 2 h. The solvent was removed to give the product.

1.20 Preparation of A110

1.20.1 Preparation of Compound 2

To a solution of Compound 1 (4.0 g, 0.024 mmol) in CH₂Cl₂ (40 mL) wasadded m-CPBA (0.3 mol) at room temperature, and the mixture was stirredat rt for 12 hours. The mixture was quenched with Na₂SO₃, washed withNaHCO₃, and concentrated to give the compound 2 (4.4 g, 100%). ¹H NMR(400 MHz, CDCl₃): 6 ppm: 3.73 (m, 2H), 3.60 (m, 2H), 3.23 (m, 2H), 1.37(s, 9H).

1.20.2 Preparation of Compound 3

To a solution of Compound 2 (2.0 g, 0.01 mmol) in Et₃N (20 mL) was addedpyridine. HF Py (3 mL) at 0° C., and the mixture was heated to 80° C.for 12 hours. Then the mixture was concentrated in vacuo. The residuewas diluted with AcOEt, washed with aqueous NH₄Cl solution and brine,dried over Na2SO4 and concentrated in vacuo. The residue was purified bycolumn chromatography (PE:EA=4:1) to give the desired product.

1.20.3 Preparation of A110

To a solution of compound 3 (0.5 g, 0.002 mol) in anhydrous DCM (2 mL)was added TFA (2 mL) at 0° C. The formed mixture was stirred for 2 h,and concentrated to give the desired product which was used for the nextstep (500 mg, 100%).

1.21 Preparation of A111

1.21.1 Preparation of Compound 2

To a solution of compound 1 (4 g, 0.02 mol) in DCM (40 mL) was addedTMSOTf (6.6 g, 0.03 mol), Et₃N (6.0 g, 0.06 mol) at room temperature.The reaction mixture was stirred for 1 hour. Then the mixture reactionwas concentrated, purified by column chromatography (PE:AcOEt=10:1) togive the compound 2 (4.3 g, 80%). ¹H NMR (400 MHz, CDCl₃): δ ppm: 4.79(s, 1H), 3.87 (m, 2H), 3.52 (m, 2H), 2.11 (s, 1H), 1.43 (s, 9H), 0.16(s, 9H).

1.21.2 Preparation of Compound 3

A mixture of Compound 2 (250 mg, 0.92 mmol), select F (360 mg, 0.92mmol) in MeCN (20 mL) was stirred for 4 hours. The mixture wasconcentrated and purified by column chromatography (PE:AcOEt=4:1) togive the compound 3 (180 mg, 90%). ¹H NMR (400 MHz, CDCl₃): δ ppm:4.10-4.84 (m, 1H), 3.63˜3.66 (m, 1H), 3.14˜3.21 (m, 1H), 2.48˜2.52 (m,1H), 2.35˜2.39 (m, 2H), 1.42 (s, 9H).

1.21.3 Preparation of Compound 4

To a solution of Compound 3 (1 g, 4.6 mmol) in ethanol (10 mL) was addedNaBH₄ (0.3 g, 7.8 mmol) slowly at 0° C. The reaction mixture was stirredat 0° C. for 0.5 h and the stirred at room temperature for 4 hours. Thereaction mixture was quenched with aqueous NH4Cl solution and extractedwith AcOEt. The organic layer was dried and concentrated to give thedesired product.

1.21.4 Preparation of Compound A111

To a solution of compound 4 (0.6 g, 2.7 mmol) in anhydrous DCM (4 mL)was added TFA (4 mL) at 0° C. The formed mixture was stirred for 2 h,and concentrated to give the desired product which was used for the nextstep (600 mg, 100%).

2 Preparation of Region B Intermediates

2.1 Preparation of B02,03,06,07,08,09,17,18

To chlorosulfonic acid (23.8 mL, 350 mmol) cooled to 0° C. was addedportionwise 2-fluorobenzoic acid (5 g, 35 mmol). After completeaddition, the yellow solution was allowed to warm to room temperature,then heated to 75° C. overnight. The reaction mixture was cooled to roomtemperature and then added dropwise to ice-water (150 mL). The whiteprecipitate was filtered, washed with water, and dried in vacuo toafford the desired product B02 as a white solid (3.37 g, 40.4%).

B03,06,07,08,09,17,18 were prepared following the same procedure as B02.

B06/07/08/09 were produced under much higher temperature, such as140-150° C., and longer reaction time, such as 6-12 h.

2.2 Preparation of B11

Chlorosulphonic acid (8.5 mL, 130 mmol) was added to a solution ofcompound 1 (5.0 g, 34 mmol) in DCM (30 mL) at −50 under N2, and stirredat rt overnight. The reaction mixture was then poured into ice water,extracted with DCM, and the organic phase was dried over Na2SO4, andconcentrated in vacuo. The residue was purified by chromatography togive a mixture of desired product (1.6 g, containing an 3-positionisomeric side product, which was used in the next step withoutseparation).

3 Preparation of Region C Intermediates

3.1 Preparation of C59

3.1.1 Preparation of Compound 2

To a solution of Compound 1 (5.0 g, 32.7 mmol) in anhydrous DCM (50 mL)was added DAST (5.5 g, 34.3 mmol) drop-wise at −78° C. under N₂. Afteraddition, the reaction mixture is allowed to warm back to rt and pouredinto a beaker containing 30 g of ice, decomposing any unreacted DAST.The organic layer is separated, and the water layer is extracted twicewith 45 mL portions of DCM. The combined organic layer was washed with50 mL of water, and dried over anhydrous magnesium sulfate. Evaporationto dryness under reduced pressure gives crude product which was purifiedby silica gel chromatography (eluted with PE:EA=100:1) to affordCompound 2. (3.5 g, yield: 70%)

3.1.2 Preparation of C59

A solution of Compound 2 (3.5 g, 22.6 mmol), Fe powder (6.3 g, 0.11 mol,5 eq.) and NH₄Cl (5.9 g, 0.11 mol) in MeOH (40 mL) and water (10 mL) washeated to reflux for 3 h. The mixture was filtered. The filtrate wasconcentrated in vacuo, and extracted with DCM. The organic phase wasconcentrated in vacuo, and purified through column chromatography.

3.2 Preparation of C60

3.2.1 Preparation of Compound 2

A mixture of Compound 1 (9.6 g, 56.8 mmol) in MeOH (100 mL) was addedNaBH₄ in portions at 0° C. After addition, the reaction mixture wasstirred for 1 h at rt.

The reaction mixture was quenched with 1 N HCl, and concentrated invacuo. The residue was extracted with EtOAc (100 mL3). The organic layerwas concentrated to give the crude product, which was used for the nextstep directly. (9.8 g, crude)

3.2.2 Preparation of Compound 3

To a solution of Compound 2 (6.2 g, 36.3 mmol) in anhydrous DCM (80 mL)was added DAST (11.7 g, 34.3 mmol) drop-wise at −78° C. under N₂. Thereaction mixture was stirred at rt for 2 h, and poured into a beakercontaining 30 g of ice, decomposing any unreacted DAST. Mixture wasextracted twice with 45 mL portions of DCM. The combined organic layerwas washed with 50 mL of water, and dried over anhydrous magnesiumsulfate. Evaporation to dryness under reduced pressure gives crudeproduct which was purified by silica gel chromatography (eluted withPE:EA=from 100:1 to 50:1) to afford Compound 3. (4.5 g, yield: 71%)

3.2.3 Preparation of C60

A solution of Compound 2 (4.2 g, 24.3 mmol) Fe powder (7.0 g, 0.12 mol,5 eq.) and NH₄Cl (6.8 g, 0.12 mol) in MeOH (40 mL) and water (10 mL) washeated to reflux for 3 hours. Filtered, the filtrate concentrated invacuo to give a solid, which was used for the next step directly.

3.3 Preparation of C61

3.3.1 Preparation of Compound 2

To a solution of Compound 1 (0.5 g, 3.3 mmol) in anhydrous DCM (10 mL)was added DAST (1.3 g, 7.95 mmol) drop-wise at −78° C. under N₂. Thereaction mixture was stirred at rt for 2 h, and poured into a beakercontaining 5 g of ice, decomposing any unreacted DAST. The mixture wasextracted twice with DCM (45 mL). The combined organic layer was washedwith 50 mL of water, and dried over anhydrous magnesium sulfate.Evaporation to dryness under reduced pressure gives crude product whichwas purified by silica gel chromatography (eluted with PE:EA=100:1) toafford Compound 2 (0.45 g, yield: 79%).

3.3.2 Preparation of C61

A solution of Compound 2 (0.45 g, 2.9 mmol) and Pd/C (50 mg) in EtOH (5mL) was stirred at rt under H2 atmosphere overnight. The Pd/C wasremoved by filtered. The filtrate was concentrated in vacuo to give thedesired product, which was used for the next step directly.

3.4 Preparation of C62

3.4.1 Preparation of Compound 2

To a solution of compound 1 (3.0 g, 17.8 mmol) in anhydrous DCM (50 ml)was added DAST (6.3 g, 39.0 mmol) at 0° C. under N₂. The formed mixturewas stirred at rt for 2 h, quenched by saturated NaHCO₃ solution, anddiluted with EA (100 mL). The organic layer was separated, dried overNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby flash column chromatograph on silica gel (PE:EA 5:1 to 3:1) to givecompound 2 (3.2 g, 94.1%).

3.4.2 Preparation of C62

A solution of compound 2 (3.2 g, 16.8 mmol), Zn ((10.9 g, 168 mmol), andNH4Cl (9.0 g, 168 mmol) was stirred in water (20 mL) and methanol (50mL) at 50 r for 4 h. The mixture was filtrated, and concentrated undervacuum. The residue was purified by silica gel chromatography to givedesired product (2.6 g, 96.3%). LCMS: 162 [M+1].

3.5 Preparation of C58

A solution of Compound 1 (5.0 g, 25.83 mmol), Fe powder (14.47 g, 258.3mmol, 10 eq.) and NH₄Cl (13.95 g, 258.3 mmol) in EtOH (80 mL) and water(10 mL) was heated to reflux for 3 h. The reaction mixture was filteredand concentrated. The residue was dissolved in water (50 mL) andextracted with ethyl acetate (50 mL2). The organic layer was dried andconcentrated to give the product used in the next step directly. LCMS:164[M+1].

3.6 Preparation of C64/65

3.6.1 Preparation of Compound 2

Compound 1 (5.0 g, 3.5 mmol) was dissolved in concentrated H₂SO₄ (16 mL)and heated to 60° C. N-bromosuccinimide (7.5, 4.2 mmol) was added inthree portions over a period of 30 min After being heated for 3 h underN₂, the reaction mixture was poured into ice water. The product wasextracted with EtOAc, washed with water and brine, and dried overNa₂SO₄. Purification by silica gel column chromatography (0-10% EtOAc inPE) yielded an orange liquid as product 2 in 45% yield. ¹H NMR (400 MHz,CDCl₃) δ 10.31 (d, 1H, J=1.2 Hz), 7.80-7.99 (m, 1H), 7.64-7.60 (m, 1H).

3.6.2 Preparation of Compound 3

A mixture of compound 2 (1.0 g, 4.5 mmol), NH₂Boc (660 mg, 5.7 mmol),Cs₂CO₃ (2.05 g, 6.3 mmol), Pd₂(dba)₃ (124 mg, 0.135 mmol) and X-Phos(193 mg, 0.405 mmol) in 30 mL of dioxane was heated to 100° C.overnight. After cooling to rt, the aqueous was extracted with EA forthree times. The organic layer was washed with water and brine, driedover Na₂SO₄, filtered and evaporated to give crude product, which waspurified by silica gel column chromatography (0-10% EtOAc in PE) to give3 (300 mg, 13%). LCMS: 258 [M+1].

3.6.3 Preparation of Compound 4

To a solution of Compound 3 (500 mg, 1.95 mmol) in anhydrous DCM (10mL), was added DAST (1.25 g, 7.78 mmol, 4.0 eq) dropwise at −78° C.under N₂. After addition, the solution was warmed to rt gradually andstirred for 2 h. The mixture was quenched with saturated NaHCO₃ (30 mL),extracted with DCM (10 mL3). The combined the organic phase was washedwith brine, dried over Na₂SO₄ and concentrated in vacuo to afforddesired product 4 (380 mg, 70%). LCMS: 280.1 [M+1].

3.6.4 Preparation of C64

To a solution of Compound 4 (280 mg, 1.0 mmol) in DCM (5 mL) was addedTFA (5 ml). The formed mixture was stirred overnight at roomtemperature. The reaction mixture was concentrated to give the crudeproduct G (145 mg, 81%). ¹H NMR (400 MHz, CDCl₃) δ 6.94-6.67 (t, 1H),5.58-6.54 (m, 2H), 3.75 (br, 2H) LCMS: 180.1 [M+1].

3.6.5 Preparation of Compound 5

To a solution of compound 2 (1.0 g, 3.5 mmol) in MeOH (20 mL) was addedNaBH₄ (200 mg, 5.0 mmol) slowly at 0° C. The reaction mixture wasstirred at 0° C. for 0.5 h and then stirred at RT for 2 h. The reactionmixture was quenched with 1N HCl (20 mL) and concentrated in vacuo. Theresidue was extracted with DCM (30 mL3). The organic layer was dried andconcentrated to give the product 5 (1.05 g, crude).

3.6.6 Preparation of Compound 6

To a solution of Compound 5 (2.0 g, 9.0 mmol) and TEA (1.36 g, 13.5mmol) in anhydrous THF (20 mL), AcCl (0.85 g, 10.8 mmol) was addeddropwise at 0° C. After addition, the solution was allowed to warm tort, and stirred for 2 h. The reaction was dissolved with EtOAc (100 mL),washed with 1 N HCl, 5% NaOH and brine, dried over Na₂SO₄ andconcentrated in vacuo to afford desired product 6 (2.3 g, 96%). LCMS:265/267 [M+1].

3.3.7 Preparation of Compound 7

A mixture of Compound 6 (6.0 g, 22.3 mmol), NH₂Boc (3.3 g, 27.9 mmol,1.2 eq.), Cs₂CO₃ (10.2 g, 31.2 mmol), Pd₂(dba)₃ (613 mg, 0.7 mmol, 3%)and Xant-Phos (955 mg, 2.01 mmol, 9%) in 200 mL of dioxane was heated to100° C. for overnight. After cooling to rt, the mixture was filtered,and the filterate was concentrated in vacuo. The residue was purified bysilica gel column chromatography (0-10% EtOAc in PE) to afford 7 (4.5 g,66% yield). LCMS: 302 [M+1].

3.3.8 Preparation of Compound 8

To a solution of Compound 7 (490 mg, 1.63 mmol) in THF (50 mL) was addedaqueous solution of NaOH (80 mg, 2.0 mmol, 10%), and stirred overnightat rt. The reaction mixture was acidified by 1N HCl solution andconcentrated in vacuo. The residue was extracted with EA. The organiclayer was washed with water and brine, dried over Na₂SO₄ andconcentrated in vacuo to afford desired product 8 (380 mg, 90%). ¹H NMR(400 MHz, CDCl₃) δ 7.38-7.33 (m, 1H), 7.07-7.05 (m, 1H), 4.75 (s, 2H),1.51 (s, 9H). LCMS: 260 [M+1].

3.3.9 Preparation of Compound 9

To a solution of Compound 8 (380 mg, 1.47 mmol) in anhydrous DCM (5 mL),DAST (473 mg, 2.94 mmol, 2.0 eq) was added dropwise at −78° C. under N₂.After addition, the solution was warmed to rt gradually and stirred for2 h. The reaction mixture was poured into sat. NaHCO₃ (20 mL) at 0° C.,extracted with DCM (10 mL3). The combined organic phase was washed withbrine, dried over Na₂SO₄, and concentrated to afford desired product 9(370 mg, 96%). LCMS: 262 [M+1].

3.3.10 Preparation of C65

To a solution of Compound 9 (370 mg, 1.7 mmol) in DCM (5 mL) was addedTFA (5 mL). The formed mixture was stirred overnight at rt. The reactionmixture was concentrated in vacuo to give the crude product C65 (130 mg,58%). ¹H NMR (400 MHz, CDCl₃) δ 6.42-6.38 (m, 2H), 5.38 (d, J=1.2 Hz,1H), 5.26 (d, 2H, J=1.2 Hz) LCMS: 162 [M+1].

Part II General Procedure for Targets General Procedure A

1.1 General Procedure for Preparation of Compound 2

A mixture of Compound 1 (4.53 mmol) in SOCl₂ (10 mL) was heated toreflux overnight. The mixture was concentrated to give the crudeproduct, which was used for the next step directly.

1.2. General Procedure for Preparation of Compound 3

To a boiled solution of Compound 2 (1.08 g, 4.52 mmol) in toluene (10mL) was added aniline (4.52 mmol), and refluxed for 2 h. The mixture wasconcentrated in vacuo to give a solid, which was used for the next stepdirectly.

1.3 General Procedure for Preparation of iii

To a solution of Compound 3 (0.3 mmol) in CH₂Cl₂ (3 mL) was added amine(0.3 mmol) and Et₃N (30 mg, 0.33 mmol) at rt, and the mixture wasstirred at rt for 2 h. The mixture was diluted with CH₂Cl₂ (20 mL) andwashed with water. The organic phase was concentrated in vacuo to givethe crude product, which was purified by prep-HPLC to give the desiredproduct.

General Procedure B

1.1 General Procedure for Preparation of Compound 2

To a solution of Compound 1 (10 mmol) in CH₂Cl₂ (50 mL) was added amine(10 mmol) and TEA (11 mmol), and stirred at rt overnight. The mixturewas washed with 1 N HCl and saturated NaHCO3, and concentrated in vacuo.The residue was purified by chromatography to give the desire product.

1.2 General Procedure for Preparation of Compound 3

To a solution of Compound 2 (5 mmol) in MeOH (40 mL) was added anaqueous solution of NaOH (7 mmol, 1N), and stirred at rt overnight. Thereaction mixture was acidified by 1N HCl solution to pH 6 and extractedwith DCM. The combined organic phase was concentrated in vacuo to givethe product.

1.3 General Procedure for Preparation of iii

To a solution of Compound 3 (1 mmol) and aniline (1 mmol) in DCM (10 mL)was added HATU (1.1 mmol), followed by DIPEA (1.5 mmol). The formedmixture was stirred at rt overnight. The mixture was diluted with CH₂Cl₂(20 mL) and washed with water. The organic layer was concentrated togive the crude product, which was purified by preparative HPLC to givethe desired product.

General Procedure C

1.1 General Procedure for Preparation of Compound 2

To a solution of Compound 1 (1.80 g, 10 mmol) and piperidine (2.1 g, 25mmol) in DCM (50 mL) was added HATU (3.8 g, 10 mmol) a at rt. The formedmixture was stirred overnight. The mixture was washed with 1N HCl, NaOH(5%) and brine, and concentrated in vacuo to give the desired product(2.1 g, 85%). LCMS: 248 [M+1].

1.2 General Procedure for Preparation of Compound 3

To a solution of methyl Compound 2 (2.1 g, 8.5 mmol) in CH₃OH (40 mL)and H₂O (10 mL) was added LiOH H₂O (0.6 g, 15 mmol). The formed mixturewas stirred overnight. The resulting mixture was acidified by 1N HCl andconcentrated in vacuo. The residue was extracted DCM. The combinedorganic phase was concentrated in vacuo to give the crude product, whichwas used for the next step directly (1.7 g, 86%). LCMS: 234 [M+1].

1.3 General Procedure for Preparation of iii

To a solution of Compound 3 (0.3 mmol), amine (0.3 mmol) and Et₃N (30mg, 0.33 mmol) in CH₂Cl₂ (3 mL) was added HATU (0.33 mmol), and themixture was stirred at rt for 2 h. The mixture was diluted with CH₂Cl₂(20 mL) and washed with water. The organic phase was concentrated invacuo to give the crude product, which was purified preparative HPLC togive the desired product.

General Procedure D

1.1 General Procedure for Preparation of Compound 2

To a solution of methyl 4-formylbenzoate (150 mg, 0.914 mmol),azetidin-3-ol hydrochloride (120 mg, 1.10 mmol) and Et₃N (111 mg, 1.10mmol) in CH₂Cl₂ (3 mL) was added NaBH(OAc)₃ (580 mg, 2.74 mmpl) Theformed mixture was stirred at rt overnight. The reaction was quenched byNaHCO₃ solution, and the formed mixture was extracted with CH₂Cl₂ (10mL×3). The organic layer was concentrated to give the crude product,which was purified preparative TLC to give the desired product (150 mg,74%). ¹H NMR (400 MHz, CDCl₃): δ ppm: 7.97 (d, 2H), 7.34 (d, 2H), 3.89(s, 3H), 3.68 (s, 2H), 3.63 (m, 2H), 3.04 (m, 2H).

1.2 General Procedure for Preparation of Compound 3

To a solution of methyl 4-((3-hydroxyazetidin-1-yl)methyl)benzoate (150mg, 0.68 mmol) in CH₃OH (3 mL) and H₂O (1 mL) was added LiOH H₂O (57 mg,1.36 mmpl) The formed mixture was stirred overnight. The resultingmixture was acidified by 1N HCl and concentrated in vacuo. The residuewas extracted DCM. The combined organic phase was concentrated in vacuoto give the crude product, which was used for the next step directly(150 mg, crude).

1.3 General Procedure for Preparation of iii

To a solution of ((3-hydroxyazetidin-1-yl)methyl)benzoic acid (150 mg,0.723 mmol) and 3-bromoamine (187 mg, 1.09 mmol) in DMF (3 mL) was addedHATU (413 mg, 1.09 mmol) and DIEA (187 mg, 1.45 mmol) at rt. The formedmixture was stirred overnight. The mixture was diluted with CH₂Cl₂ (20mL) and washed with water (5 mL×2). The organic layer was concentratedto give the crude product, which was purified preparative HPLC to givethe desired product (15 mg, 6%). ¹H NMR (400 MHz, CDCl₃): δ ppm: 11.03(br, 1H), 10.49 (s, 1H), 8.11 (s, 1H), 7.98 (d, 2H), 7.75 (m, 1H), 7.67(d, 2H), 7.29 (m, 2H), 4.45 (m, 3H), 4.16 (m, 2H), 3.87 (m, 2H). LCMS:361/363 [M+1/M+1+2].

General Procedure E

1.1 General Procedure for Preparation of Compound 2

Compound 1 (1.0 g, 3.54 mmol) was dissolved in 10 g (65.22 mmol) ofPOCl₃, then, the mixture was warmed to 100° C. and stirred forovernight. Solvent was evaporated in vacuo and the residue was preparedfor next step.

1.2 General Procedure for Preparation of Compound 3

To a solution of compound 2 (138 mg, 050 mmol) in 5 mL of DCM, aniline(0.55 mmol) and Et₃N (51 mg, 050 mmol) was added. The mixture wasstirred at rt for overnight. Water was added to the mixture andextracted with DCM, the organic layer was washed with brine, dried overNa₂SO₄, filtered and solvent was evaporated in vacuo. The residue wasprepared for next step.

1.3 General Procedure for Preparation of iii

To a solution of Compound 3 (0.3 mmol) in CH₂Cl₂ (3 mL) was added amine(0.3 mmol) and Et₃N (30 mg, 0.33 mmol) at rt, and the mixture wasstirred at rt for 2 h. The mixture was diluted with CH₂Cl₂ (20 mL) andwashed with water. The organic phase was concentrated in vacuo to givethe crude product, which was purified preparative HPLC to give thedesired product.

General Procedure F

1.1 Preparation of Compound 2

To chlorosulfonic acid (65 g, 0.56 mol) cooled to 0° C. was addedportionwise Compound 1 (10.2 g, 73 mmol). After complete addition, theyellow solution was warmed to room temperature, then heated to 70° C.overnight. The reaction mixture was cooled to room temperature and thenadded drop-wise to ice (0.5 L). The white precipitate was filtered,washed with water, and dried in vacuo to afford the desired product as awhite solid (13.7 g, 80%).

1.2 Preparation of Compound 3

A mixture of Compound 2 (13.7 g, 57.6 mmol) in SOCl₂ (60 mL) was heatedto reflux overnight. The mixture was concentrated to give the crudeproduct, which was used for the next step directly.

1.3 Preparation of Compound 4

To a boiled solution of compound 3 (5.5 g, 21 mmol) in anhydrous toluene(50 mL) was added a solution of aniline (2.0 mg, 21 mmol). The formedmixture was stirred for another 30 minutes. The mixture was allowed tocool to room temperature, and diluted with EtOAc (50 mL). The mixturewas washed with ice-water (20 mL). The organic layer was concentrated togive the desired product, which was used for the next step directly (7.0g, 67%).

1.4 Preparation of Compound 5

To a solution of Compound 4 (7.0 g, 22 mmol) in dry CH₂Cl₂ (80 mL) wasadded piperidin-4-ol (2.2 g, 22 mmol) and Et₃N (3 mL) at rt. The formedmixture was stirred overnight. The mixture was diluted with CH₂Cl₂ (100mL) and washed with water (50 mL 2). The organic layer was concentratedto give the crude product, which was purified by silica chromatographygel to give the desired product (4.5 g, 53%).

1.5 Preparation of Compound 6

To a solution of Compound 5 (4.5 g, 12.1 mmol) in CH₂Cl₂ (50 mL) wasadded Et₃N (2.5 mL), followed by CH₃COCl (1.2 g, 12.1 mmol) at 0° C. Theformed mixture was stirred overnight at room temperature. The mixturewas washed with aqueous Na₂CO₃ solution, and the aqueous layer wasacidified by 1N HCl. The formed mixture was extracted with CH₂Cl₂ (100mL 3). The combined organic layers were concentrated to give crudeproduct which was purified by silica chromatography gel to give thedesired product (3.0 g, 60%).

1.6 Preparation of Compound 7

A solution of Compound 6 (310 mg, 0.73 mmol) in POCl₃ (3.5 mL) washeated to 80° C. for 3 hours. The organic layer was concentrated to givethe desired product, which was used for the next step directly (340 mg,crude)

1.7 Preparation of Compound 8

To a solution of Compound 7 (340 mg, 0.73 mmol) in anhydrous THF (5 mL)was added O-(trimethylsilyl)hydroxylamine (94 mg, 0.9 mmol) drop-wise at0° C. The formed mixture was stirred overnight at room temperature. Themixture was washed with 1N HCl solution, and the aqueous layer wasacidified by aqueous Na₂CO₃. The formed mixture was extracted withCH₂Cl₂ (10 mL 3). The combined organic layers were concentrated to givecrude product. (360 mg, crude)

1.8 Preparation of Compound 9

To a solution of Compound 8 (360 mg) in NMP (3 mL) was added t-BuOK (80mg, 0.71 mmol) at rt, and the mixture was heated to 80° C. for 3 h. Themixture was diluted with EtOAc (20 mL) and washed with water. Theorganic phase was concentrated in vacuo to give the crude product, whichwas purified by preparative HPLC to give the desired product. (50 mg,yield: 20%)

1.9 Preparation of 738

A solution of Compound 9 (50 mg, 0.12 mmol), NaOH (10 mg, 0.24 mml), in1 mL of MeOH and 1 ml of water was stirred at room temperature for 16hours. The solvent was removed off and purified by Prep-HPLC to afford20 mg of 738 (20 mg, 40%). LCMS: 374 [M+1].

737 was prepared following the similar procedure with 738.

General Procedure G

1.1 Preparation of Compound 2

To chlorosulfonic acid (82.4 g, 0.71 mol) cooled to 0° C. was addedportionwise Compound 1 (5.0 g, 25 mmol). After complete addition, theyellow solution was warmed to room temperature, then heated to 150° C.for 5 h. The reaction mixture was cooled to room temperature and thenadded drop-wise to ice (60 g). The white precipitate was filtered,washed with water, and dried in vacuo to afford the desired product as ayellow solid (6.0 g, 80%).

¹H NMR (400 MHz, CDCl₃): δ ppm: 8.89 (d, J=2.0 Hz 1H), 8.25 (dd, J=2.0,8.4 Hz, 1H), 8.02 (d, J=8.4 Hz, 1H).

1.2 Preparation of Compound 3

A mixture of Compound 2 (6.0 g, 20.1 mmol) in SOCl₂ (60 mL) was heatedto reflux for 3 h. The mixture was concentrated to give the crudeproduct, which was used for the next step directly. To a boiled solutionof compound 3 (6.4 g, 20.1 mmol) in anhydrous toluene (60 mL) was added3,4,5-trifluoroaniline (2.9 g, 20.1 mmol). The formed mixture was heatedto 100° C. for 6 h. The mixture was allowed to cool to room temperature,and then concentrated to give the desired product, which was used forthe next step directly (7.5 g, 87%).

¹H NMR (400 MHz, DMSO): δ ppm: 10.78 (s, 1H), 8.45 (d, J=2.0 Hz, 1H),7.75 (m, 4H).

1.3 Preparation of Compound 6

To a solution of Compound 4 (2.0 g, 4.7 mmol) in MeCN (20 mL) was addedpiperidin-4-ol (0.47 g, 4.7 mmol) and Et₃N (1.4 mL) at rt. The formedmixture was stirred for 2 h. The mixture was diluted with EA (150 mL)and washed with water (50 mL 2). The organic layer was concentrated togive the crude product, which was purified by silica chromatography gelto give the desired product (1.7 g, 74%).

1.4 Preparation of 927

To a solution of Compound 6 (200 mg, 0.41 mmol) in MeOH (10 mL) wasadded Et₃N (165 mg, 1.62 mmol) and Pd(dppf)Cl₂ (33 mg, 0.04 mmol) underN₂. The formed mixture was stirred at 80° C. under CO of 50 Psi pressurefor 12 h. The mixture was allowed to cool to room temperature andfiltered. The filtration was concentrated and purified by silicachromatography gel to give the desired product (150 mg, 79%). LCMS:473.1 [M+1].

¹H NMR (400 MHz, DMSO): δ ppm: 10.86 (s, 1H), 8.31 (s, 1H), 8.29 (s,1H), 7.85 (d, J=7.6 Hz, 1H), 7.72 (t, J=5.0 Hz, 2H), 4.73 (d, J=4.0 Hz,1H), 3.86 (s, 3H), 3.61 (m, 1H), 3.35 (m, 2H), 2.95 (m, 2H), 1.75 (m,2H), 1.38 (m, 2H).

1.5 Preparation of 1420

To a solution of Compound 927 (200 mg, 0.42 mmol) in THF (10 mL) wasadded LiBH₄ (38 mg, 1.72 mmol) under N₂ at 0° C., the formed mixture wasstirred at room temperature overnight. The reaction mixture was dilutedwith EA (100 mL) and washed with brine (50 mL 2). The organic layer weredried over Na₂SO₄, concentrated and purified by silica chromatographygel to give the desired product (45 mg, 24%). LCMS: 445.1 [M+1].

¹H NMR (400 MHz, CD3OD): δ ppm: 8.42 (d, J=2.0 Hz, 1H), 8.21 (dd, J=2.0,8.4 Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.63 (m, 2H), 5.06 (s, 2H), 3.76(m, 1H), 3.53 (m, 2H), 3.05 (m, 2H), 1.90 (m, 2H) 1.59 (m, 2H).

Specific Experimental Procedure for Preparation of 777

1.1 Preparation of Compound 2

To chlorosulfonic acid (23.8 mL, 350 mmol) was added portionwise2-fluorobenzoic acid (5 g, 35 mmol) at 0° C. After addition, the yellowsolution was allowed to warm to room temperature, and then heated at 75°C. for 12 h. The reaction mixture was cooled to room temperature andthen poured onto ice water (150 mL). The white precipitate was filtered,washed with water, and dried in vacuo to afford the desired product(3.37 g, 40.4%).

1.2 Preparation of Compound 3

A mixture of Compound 2 (238 mg, 1 mmol) in SOCl₂ (10 mL) was heated atreflux for 12 h. The mixture was concentrated to give the crude product,which was used for the next step directly.

1.3 Preparation of Compound 5

To a solution of Compound 3 (260 mg, 1 mmol) in refluxing toluene (10mL) was added Compound 4 (147 mg, 1 mmol). The resulting solution washeated at reflux for 2 h and then concentrated in vacuo to give a solid,which was used for the next step directly without purification.

1.4 Preparation of 777

To a solution of crude Compound 5 (370 mg, 1 mmol) and Compound 6 (101mg, 1 mmol) in MeCN (15 mL) was added Et₃N (150 mg, 1.5 mmol) at roomtemperature. After addition, the resulting mixture was stirred for 2 h,at which time LCMS indicated the completion of the reaction. Thesolution was evaporated and the residue was purified by preparative HPLCto give the desired product 777 (251 mg, 61%).

¹H NMR (400 MHz, MeOD) δ 8.11-8.14 (m, 1H), 8.00-8.03 (m, 1H), 7.51-7.59(m, 3H), 3.66-3.71 (m, 1H), 3.36-3.42 (m, 2H), 2.85-2.91 (m, 2H),1.89-1.94 (m, 2H), 1.15-1.64 (m, 2H). LCMS: 433 [M+1].

Specific Experimental Procedure for Preparation of Compound 890

1.1 Procedure for Preparation of Compound 2

A mixture of Compound 1 (10.0 g, 42.0 mmol) in SOCl₂ (60 mL) was heatedto reflux overnight. The mixture was concentrated in vacuo. The residuewas dissolved with toluene (30 mL), and concentrated in vacuo to givethe crude product, which was used for the next step directly.

1.2 Procedure for Preparation of Compound 3

To a boned solution of crude compound 2 (42 mmol) in toluene mL) wasadded a suspension of aniline (6.17 g, 42 mmol) in toluene (40 mL)slowly, and refluxed for 2 h. The mixture was concentrated in vacuo togive a solid, which was used for the next step directly.

1.3 Procedure for Preparation of 890

To a solution of Compound 3 (42 mmol) in MeCN (250 mL) was added amine 4(4.3 g, 42 mmol) and Et₃N (6.18 g, 61.2 mmol) at rt, and the mixture wasstirred at rt for 3 h. The solution was concentrated in vacuo. Theresidue was purified by silica gel chromatography to give the desiredproduct as white solid (15.7 g, 86.5%).

H-NMR (Methanol-d4 400 MHz): 8.41-8.39 (dd, J=6.5, 2.4 Hz, 1H),8.26-8.23 (m, 1H), 7.61-7.50 (m, 3H), 3.74-3.72 (m, 1H), 3.56-3.52 (m,2H), 3.06-3.01 (m, 2H), 1.91-1.87 (m, 2H), 1.59-1.56 (m, 2H).

LCMS: 433.0 [M+1].

Specific Experimental Procedure for Preparation of 894

1.1 Procedure for Preparation of Compound 2

A mixture of Compound 1 (3.0 g, 12.6 mmol) in SOCl₂ (80 mL) was heatedto reflux overnight. The mixture was concentrated in vacuo. The residuewas re-dissolved with toluene (30 mL), and concentrated in vacuo to givethe crude product, which was used for the next step directly.

1.2 Procedure for Preparation of Compound 3

To a solution of crude Compound 2 (12.6 mmol) in refluxing toluene (10mL) was added 3,4-difluoroaniline (1.6 g, 12.6 mmol). The resultingsolution was heated at reflux for 2 h and then concentrated in vacuo togive a solid, which was used for the next step directly withoutpurification.

1.3 Procedure for Preparation of 894

To a solution of crude Compound 3 (600 mg, 2.0 mmol) and Compound 4 (203mg, 2.0 mmol) in MeCN (10 mL) was added Et₃N (303 mg, 3.0 mmol) at roomtemperature. The mixture was stirred at rt for 3 h, at which time LCMSindicated the completion of the reaction. The solution was concentratedin vacuo. The residue was purified by prep-HPLC to give the desiredproduct as white solid (430 mg, 60.3%). H-NMR (Methanol-d4 400 MHz):8.40-8.42 (m, 1H), 8.23-8.25 (m, 1H), 7.75-7.82 (m, 1H), 7.42-7.52 (m,2H), 7.25-7.28 (m, 1H), 3.74-3.74 (m, 1H), 3.52-3.56 (m, 2H), 3.01-3.07(m, 2H), 1.1.87-1.91 (m, 2H), 1.56-1.59 (m, 2H). LCMS: 415.0 [M+1].

Experimental Procedure for Preparation of Compound 891

1.1 Procedure for Preparation of Compound 2

A mixture of Compound 1 (20.0 g, 84.0 mmol) in SOCl₂ (120 mL) was heatedat reflux for 3 h. The mixture was concentrated in vacuo. The residuewas dissolved with toluene (60 mL), and concentrated in vacuo to givethe crude product, which was used for the next step directly.

1.2 Procedure for Preparation of Compound 3

To a solution of crude Compound 2 (84 mmol) in refluxing toluene (200mL) was added 3-chloro-4-fluoroaniline (12.3 g, 42 mmol). The resultingmixture was refluxed for 5 h. The mixture was concentrated in vacuo togive a solid, which was used for the next step directly.

1.3 Procedure for Preparation of Compound 891

To a solution of crude Compound 3 (2.0 g, 5.5 mmol) and Compound 4 (0.55g, 5.5 mmol) in MeCN (30 mL) was added Et₃N (0.83 g, 8.2 mmol) at rt.The mixture was stirred at rt for 2 h, at which time LCMS indicated thecompletion of the reaction. The solution was concentrated in vacuo. Theresidue was purified by silica gel chromatography to give the desiredproduct as white solid (1.41 g, 60.3%).

H-NMR (DMSO-d6 400 MHz): 10.66 (s, 1H), 8.37-8.33 (m, 2H), 8.04-8.02 (m,1H), 7.72-7.62 (m, 2H), 7.47-7.38 (m, 1H), 4.75-4.74 (d, J=4.0 Hz, 1H),3.65-3.55 (m, 1H), 3.37-3.27 (m, 2H), 2.98-2.88 (m, 2H), 1.75-1.65 (m,2H), 1.45-1.35 (m, 2H). LCMS: 431.0 [M+1].

Specific Experimental Procedure for Preparation of Compound 903

To a solution of Compound 1 (4.5 g, 12.2 mmol) and Compound 2 (1.5 g,12.2 mmol) in MeCN (70 mL) was added Et₃N (3.1 g, 30.7 mmol) at rt. Themixture was stirred at rt for 2 h, at which time LCMS indicated thecompletion of the reaction. The solution was concentrated in vacuo. Theresidue was purified by silica gel chromatography to give the desiredproduct as white solid (2.69 g, 52.7%).

H-NMR (Methanol-d4 400 MHz): 8.59-8.33 (m, 1H), 8.13-8.10 (m, 1H),7.51-7.42 (m, 2H), 7.41-7.35 (m, 1H), 4.27-4.24 (m, 1H), 3.42-3.37 (m,3H), 3.25-3.20 (m, 1H), 1.90-1.86 (m, 1H), 1.82-1.78 (m, 1H).

LCMS: 419.0 [M+1].

Experimental Procedure for Preparation of Compound 953

To a solution of Compound 1 (5.5 g, 15.1 mmol) and Compound 2 (1.6 g,14.7 mmol) in MeCN (80 mL) was added Et₃N (3.8 g, 37.7 mmol) at rt. Themixture was stirred at rt for 2 h, at which time LCMS indicated thecompletion of the reaction. The solution was concentrated in vacuo. Theresidue was purified by silica gel chromatography to give the pureproduct as white solid (1.1 g, 18.3%) and impure product (about 1.0 g).

H-NMR (Methanol-d4 400 MHz): 8.46-8.41 (m, 1H), 8.35-8.25 (m, 1H),7.99-7.92 (m, 1H), 7.68-7.52 (m, 2H), 7.29-7.24 (t, J=8.4 Hz, 1H),4.55-4.45 (m, 1H), 4.16-4.12 (m, 2H), 3.76-3.71 (m, 2H). LCMS: 403.0[M+1].

Experimental Procedure for Preparation of Compound 960_D1 and Compound960_D2

1.1 Preparation of Compound 2

To a solution of Compound 1 (40 g, 188 mmol) in DCM (400 mL) was addedTMSOTf (44 g, 198 mmol), followed by Et₃N (38.0 g, 0.377 mol) at roomtemperature. The reaction mixture was stirred for 1 hour. Then thereaction was concentrated to give the crude product Compound 2 (48.0 g,88.8%).

¹H NMR (400 MHz, CDCl₃): δ ppm: 4.79 (s, 1H), 3.87 (m, 2H), 3.52 (m,2H), 2.11 (s, 1H), 1.43 (s, 9H), 0.16 (s, 9H).

1.2 Preparation of Compound 3

A mixture of Compound 2 (48 g, 167 mmol) and select-F (69 g, 184 mmol)in MeCN (500 mL) was stirred for 4 hours. The mixture was concentratedand purified by column chromatography (PE:AcOEt=5:1) to give thecompound 3 (14 g, 36%). ¹H NMR (400 MHz, CDCl₃): δ ppm: 4.10-4.84 (m,1H), 3.63-3.66 (m, 1H), 3.14-3.21 (m, 1H), 2.48-2.52 (m, 1H), 2.35-2.39(m, 2H), 1.42 (s, 9H).

1.3 Preparation of Compound 4

To a solution of Compound 3 (8.6 g, 36.1 mmol) in ethanol (90 mL) wasadded NaBH₄ (2.13 g, 56.7 mmol) slowly at 0° C. The reaction mixture wasstirred at room temperature for 4 hours. The reaction mixture wasquenched with aqueous NH₄Cl solution and extracted with AcOEt. Theorganic layer was dried and concentrated in vacuo. The residue waspurified by column chromatography to give the desired product as amixture of cis and trans isomers (8.3 g, 97.6%).

1.4 Preparation of Compound 5

To a solution of compound 4 (650 mg, 2.73 mmol) in anhydrous DCM (6 mL)was added TFA (4 mL). The mixture was stirred for 2 h, and concentratedto give the desired product which was used for the next step (300 mg,80%).

1.5 Preparation of 960_D1

To a solution of Compound 6 (1.54 g, 4.2 mmol) and Compound 5 (500 mg,4.2 mmol) in MeCN (25 mL) was added Et₃N (848 mg, 8.4 mmol) at rt. Themixture was stirred at rt for 3 h, at which time LCMS indicated thecompletion of the reaction. The solution was concentrated in vacuo. Theresidue was purified by preparative HPLC to give the desired product aswhite solid (580 mg, 42.3%). The first peak in HPLC is named as 960_D1,while the second peak is 960_D2 (12.83 mg, 21.2%).

960_D1: H-NMR (DMSO-d6 400 MHz): 10.79 (s, 1H), 8.37-8.29 (m, 2H),7.72-7.68 (m, 3H), 5.17-5.16 (d, J=4.0 Hz, 1H), 4.71-4.58 (m, 1H),3.69-3.53 (m, 3H), 3.200-3.10 (m, 1H), 2.95-2.93 (m, 1H), 1.71-1.66 (m,2H). LCMS: 451.1 [M+1].

960_D2: H-NMR (DMSO-d6 400 MHz): 10.82 (s, 1H), 8.38-8.32 (m, 2H),7.75-7.69 (m, 3H), 5.39-5.38 (d, J=4.0 Hz, 1H), 4.48-4.67 (d, J=4.0 Hz,1H), 3.71 (s, 1H), 3.35 (s, 2H), 3.23-3.20 (t, J=4.0 Hz, 2H), 1.88-1.85(m, 1H), 1.56-1.52 (m, 1H). LCMS: 451.1 [M+1].

Specific Experimental Procedures for Preparation of Compounds 1161/911

1.1 Preparation of Compound 2

To CH₃MgBr (3 M, 60 mmol) in THF (50 mL) was added a solution ofCompound 1 (10.0 g, 53 mmol) in THF (50 mL) slowly at 0-4° C. Theresulting mixture was stirred at rt for 1 h. The reaction mixture wasquenched by NH₄Cl solution, and extracted with EtOAc (100 mL×3). Theorganic layer was concentrated to give the crude product, which waspurified by column chromatography to give the desired product (2.24 g,Yield: 20.7%). LCMS: 206.0 [M+1].

1.2 Preparation of Compound 3

To a solution of Compound 2 (2.26 g, 11 mmol) in MeOH (40 mL) was addedPd(OH)₂ (350 mg), and was stirred under H₂ at 50 psi for 72 h. Themixture was filtered and the filtrate was concentrated to give thedesired product (1.26 g, Yield: 100%).

H-NMR (CDCl3 400 MHz): 2.85-2.91 (m, 2H), 2.70-2.76 (m, 2H), 2.47-2.51(m, 4H), 1.18 (s, 3H).

1.3 Procedure for Preparation of Compound 1161

To a solution of Compound 3 (350 mg, 3 mmol) and Compound 4 (1.28 g, 3.5mmol) in MeCN (15 mL) was added Et₃N (2 mL) at rt. The mixture wasstirred at rt for 1 h. The reaction mixture was dissolved with EA (150mL) and washed with brine (70 mL*2). The organic layer were dried overNa₂SO₄, concentrated in vacuo and purified by silica chromatography gelto give the desired product (652 mg, 48.7%).

¹H NMR (Methanol-d4 400 MHz): 8.43-8.41 (dd, J=6.5, 2.4 Hz, 1H),8.27-8.25 (m, 1H), 7.65-7.60 (m, 2H), 7.55-7.50 (dd, J=9.8, 8.8 Hz, 1H),3.60-3.57 (m, 2H), 3.04-2.97 (m, 2H), 1.68-1.63 (m, 4H), 1.22 (s, 3H).LCMS: 447.0 [M+1].

1.4 Procedure for Preparation of 911

To a solution of Compound 3 (335 mg, 2.9 mmol) in MeCN (14 mL) was addedCompound 5 (1.22 g, 3.4 mmol) and Et₃N (2 mL) at rt, and the mixture wasstirred at rt for 1 h. The reaction mixture was diluted with EA (150 mL)and washed with brine (70 mL*2). The organic layer were dried overNa₂SO₄, concentrated and purified by silica chromatography gel to givethe desired product (686 mg, 54.9%).

H-NMR (Methanol-d4 400 MHz): 8.44-8.41 (dd, J=6.5, 2.1 Hz, 1H),8.28-8.25 (m, 1H), 7.99-7.97 (dd, J=6.8, 2.5 Hz, 1H), 7.65-7.62 (m, 1H),7.54-7.50 (t, J=9.3 Hz, 1H), 7.29-7.24 (t, J=9.0 Hz, 1H), 3.60-3.57 (m,2H), 3.04-2.98 (m, 2H), 1.72-1.65 (m, 4H), 1.22 (s, 3H). LCMS: 445.0[N4+1]/447.0 [M+3].

Experimental Procedure for Preparation of Compound 916

1.1 Preparation of Compound 2

To a solution of Me₃SOI (87.5 g, 396 mmol) in DMSO (400 mL) was addedNaH (17 g, 706 mmol) at 0° C., and stirred at room temperature for 1 h.Then Bu₄NBr (8.05 g, 26 mmol) was added to the solution, followed by asolution of Compound 1 (50.0 g, 265 mmol) in DMSO (200 mL), and themixture was stirred at room temperature for 1.5 h. The mixture waspoured into water slowly and extracted with EA. The combined organicphases were washed with brine, dried over Na₂SO₄, and concentrated invacuo to give the desired product (50.5 g, 93%).

¹H NMR (400 MHz, CDCl₃): δ: 7.28-7.17 (m, 5H), 2.57-2.45 (m, 6H),1.77-1.74 (m, 2H), 1.50-1.46 (m, 2H), 1.20-1.17 (m, 2H).

1.2 Preparation of Compound 3

A mixture of Compound 2 (30.5 g, 150 mmol) in H₂SO₄ (37.5 g, 380 mmol,0.2 M) was stirred at rt overnight. The mixture was neutralized withNa₂CO₃ to pH10 and extracted with EtOAc. The combined organic layerswere washed with brine, dried over Na₂SO₄ and concentrated to give thedesired product (20.0 g, 58%). ¹H NMR (400 MHz, CD₃OD): δ ppm: 7.29-7.22(m, 5H), 3.50 (s, 2H), 3.44 (s, 2H), 3.31-3.27 (m, 2H), 2.61-2.58 (m,2H), 2.41-2.36 (m, 2H), 1.69-1.64 (m, 2H), 1.51-1.49 (m, 2H).

1.3 Preparation of Compound 4

To a solution of Compound 3 (20 g, 90 mmol) in CH₃OH (800 mL) was addeddry Pd(OH)₂ (2 g). The formed mixture was hydrogenated under H₂atmosphere of 15 Psi pressure overnight. The catalyst was filtered andthe filtrate was concentrated to give the desired product (12 g, 98%).

1.4 Preparation of Compound 916

To a solution of Compound 5 (7.8 g, 21.2 mmol) in MeCN (100 mL) wasadded amine 4 (2.8 g, 21.2 mmol) and Et₃N (4.3 g, 42.4 mmol) at rt, andthe mixture was stirred at rt for 3 h. The solution was concentrated invacuo. The residue was purified by silica gel chromatography eluted withPE:EA=from 3:1 to 1:2 to give the desired product as white solid (6.2g), which was purified by re-crystallization from EA (30 mL) to affordpure product as white solid (4.1 g, yield: 41%).

¹H NMR (400 MHz, METHANOL-d4): 8.48-8.39 (m, 1H), 8.33-8.21 (m, 1H),7.63-7.59 (m, 2H), 7.59-7.52 (m, 1H), 3.72-3.69 (m, 2H), 3.35 (s, 2H),3.03-2.94 (m, 2H), 1.78-1.67 (m, 2H), 1.63-1.60 (m, 2H)

LCMS: 463.1[M+1].

Specific Experimental Procedure for Preparation of Compounds 826/922

Experimental Data:

1.1 Preparation of Compound 2

To a solution of Compound 1 (10 g, 0.06 mol) in CH₂Cl₂ (40 mL) was addedm-CPBA (9.0 g, 0.66 mol) at room temperature, and the mixture wasstirred at rt for 12 hours. The mixture was quenched with Na₂SO₃, washedwith NaHCO₃, and concentrated to give the compound 2 (10 g, 90%).

¹H NMR (400 MHz, CDCl₃): δ ppm: 3.73-3.75 (m, 2H), 3.59-3.60 (m, 2H),3.20-3.25 (m, 2H), 1.37 (s, 9H).

1.2 Preparation of Compound 3

To a solution of Compound 2 (10.0 g, 0.054 mol) in Et₃N (60 mL) wasadded Py HF (20 mL) at 0° C., and the mixture was heated to 80° C. for12 hours. Then the mixture was concentrated in vacuo. The residue wasdiluted with AcOEt, washed with aqueous NH₄Cl solution and brine, driedover Na₂SO₄ and concentrated in vacuo. The residue was purified bycolumn chromatography (PE:EA=4:1) to give the compound 3 (4 g, 36%).

¹H NMR (400 MHz, CDCl₃): δ ppm: 4.79-4.90 (m, 1H), 4.31-4.34 (m, 1H),3.46-3.56 (m, 4H), 2.25 (s, 1H), 1.40 (s, 9H).

1.3 Preparation of Compound 4

To a solution of compound 3 (2 g, 0.01 mol) in anhydrous DCM (10 mL) wasadded TFA (10 mL) at 0° C. The formed mixture was stirred for 2 h, andconcentrated to give the desired product as a TFA salt which was usedfor the next step (2.4 g).

1.4 Preparation of 826

To a solution of Compound 5 (900 mg, 2.3 mmol) and Compound 4 (580 mg)in MeCN (50 mL) was added Et₃N (690 mg, 6.9 mmol) at room temperature.The mixture was stirred at rt for 3 hours. The solution was concentratedin vacuo. The residue was purified by silica gel chromatography(PE:EA=3:1) to give 826 as white solid (0.6 g, 60%).

¹H NMR (400 MHz, Methanol-d4): δ ppm: 8.40 (s, 1H), 8.21-8.23 (d, J=7.6Hz, 1H), 8.06-8.13 (m, 2H), 7.69-8.06 (m, 2H), 4.77-4.88 (m, 1H),4.23-4.25 (m, 1H), 3.43-3.66 (m, 3H), 3.32-3.33 (m, 1H).

1.5 Preparation of 922

To a solution of Compound 6 (900 mg, 2.47 mmol) and Compound 4 (620 mg)in MeCN (50 mL) was added Et₃N (750 mg, 7.41 mmol) at room temperature.The mixture was stirred at rt for 3 hours. The solution was diluted withAcOEt, washed with water, dried with anhydrous Na₂SO₄ and concentratedin vacuo. The residue was purified by silica gel chromatography(PE:EA=3:1) to give 922 as white solid (0.6 g, 50%).

¹H NMR (400 MHz, DMSO-d6): δ ppm: 8.40 (s, 1H), 10.68 (s, 1H), 8.39-8.42(m, 2H), 8.03-8.05 (m, 1H), 7.68-7.70 (m, 1H), 7.43-7.48 (m, 1H),5.61-5.62 (d, J=3.6 Hz 1H), 4.87-5.01 (m, 1H), 4.20-4.22 (m, 1H),3.57-3.65 (m, 2H), 3.48-3.49 (m, 1H), 3.45-3.47 (m, 1H). LCMS:435.0[M+1].

Specific Experimental Procedure for Compound 958

1.1 Preparation of Compound 2

To a slurry of Compound 1 (6.5 g, 79 mmol) and Compound 2 (10.2 g, 69mmol) in MeOH (100 mL) was added an aqueous Na₂CO₃ (6 mL, 2 N, 12 mmol),and stirred at rt for 24 h. The solid was collected by filtration,washed with MeOH and dried in vacuo, which was used in the next step (14g, crude).

LCMS: 230.2 [M+1].

1.2 Preparation of Compound 4

To a mixture of Compound 3 (14 g, 61 mmol) in MeOH/THF (300 mL/50 mL)was added NaBH₄ (3.4 g, 90 mmol) at 0° C., and stirred at rt overnight.1 N HCl was added slowly to quench the reaction. The resulting mixturewas concentrated in vacuo. The residue was dissolve with water andEtOAc. The aqueous phase was extracted with EtOAc (500 mL×2). Thecombined organic phase was concentrated to give the crude product, whichwas purified by column chromatography to give the Compound 4 (8.0 g,57%). LCMS: 236.1 [M+1].

1.3 Preparation of Compound 5

A mixture of Compound 4 (8.0 g, 34 mmol) in MeOH (100 mL) was addedconcentrated HCl (10 mL), and heated to reflux for 2 h. The mixture wasconcentrated in vacuo. The residue was dissolved with water and washedwith EA. The aqueous phase was concentrated in vacuo to give the desiredproduct with HCl salt (2.8 g, 82%). ¹H NMR (400 MHz, CDCl₃): δ ppm: 4.33(bs, 1H), 3.66 (bs, 1H), 2.08-2.16 (m, 2H), 1.74-1.90 (m, 4H).

1.4 Preparation of 958

To a solution of Compound 6 (626 mg, 1.72 mmol) and Compound 5 (174 mg,1.72 mmol) in MeCN (7 mL) was added Et₃N (260 mg, 2.58 mmol) at rt, andthe mixture was stirred at rt for 2 h. The solution was concentrated invacuo. The organic phase was concentrated in vacuo to give the crudeproduct, which was purified by prep-HPLC to give the desired product(355 mg, 48%).

H NMR (MeOD-d4 400 MHz): 8.47-8.45 (m, 1H), 8.230-8.22 (m, 1H),7.98-7.96 (m, 1H), 7.62-7.61 (m, 1H), 7.50-7.48 (m, 1H), 7.46-7.26 (m,1H), 4.13-4.10 (m, 1H), 3.72-3.68 (m, 1H), 2.10-2.08 (m, 1H), 1.08-1.64(m, 4H). 1.64-1.43 (m, 1H).

LCMS: 431.0 [M+1].

Example HBV Assembly Assay

Selected compounds of the invention were assayed in the HBV assemblyassay, as described elsewhere herein. The assembly assay was conductedin 96-well plate format. The assembly reactions were carried out in 50mM Hepes buffer, pH 7.5 and 150 mM NaCl. The compounds werepre-incubated with the HBV CA protein for 15 min, and the assemblyreactions were initiated by addition of NaCl. The reaction was allowedto continue for 1 hour at room temperature. The 96-well plate assemblyassay consistently had Z′ factors greater than 0.7 and were robust andreproducible both from plate-to-plate and day-to-day.

To determine the effect on capsid assembly, each test compound wasinitially screened at 4 different concentrations: 10 μM, 3 μM, 1 μM and0.3 μM in duplicates. Primary hits were compounds that show >50%activity in the assembly assay at 10 μM and a representative group ofthese active compounds is illustrated in Table 2.

TABLE 2 “Activity” represents activity in HBV assembly assay (‘+’indicates >50% activity at 10 μM) Compound Activity Compound Activity 065 +  078 +  079 +  119 +  121 +  126 +  129 +  148 +  191 +  208 + 242 +  258 +  282 +  318 +  332 +  349 +  366 +  407 +  419 +  451 + 462 +  478 +  501 +  541 +  553 +  595 +  610D2 +  646 +  659D2 + 677R +  688 +  713D2 +  719D1 +  725D1 +  743D1 +  758 +  765 +  775 + 803 +  820D2 +  824D2 +  826 +  843 +  867D2 +  885 +  890 +  900 + 901 +  903 +  914 +  916 +  927 +  928 +  935 +  946D2 +  953 + 955D1 +  955D2 +  958 +  959 +  960D1 +  960D2 +  989D1 + 1042 + 1057 +1087 + 1094S + 1099 + 1106 + 1113 + 1114 + 1116 + 1129 + 1130 +1134CT2 + 1135D1 + 1149 + 1153 + 1157 + 1161 + 1189 + 1283 + 1338 +1339 + 1345 + 1374CT1 + 1374CT2 + 1378CT2 + 1379 + 1380 + 1404 + 1410 +1413 + 1420 +

Example Dot-Blot Assay

Selected compounds, which were shown to be active in the HBV assemblyassay, were tested for their activity and toxicity in cellular assay. Inthe first anti-viral assay, the ability of compounds to inhibit HBVreplication in an HBV-producing hepatoma cell line using the dot-blotmethod was evaluated.

Confluent monolayers of HepG2-2.2.15 cells were incubated with completemedium containing various concentrations of a test compound. Three dayslater, the culture medium was replaced with fresh medium containing theappropriately diluted test compound. Six days following the initialadministration of the test compound, the cell culture supernatant wascollected, and cell lysis was performed. The samples were applied ontoNylos membranes and DNA was immobilized to the membrane by UVcross-linking. After pre-hybridization, the HBV probe was added and thehybridization was performed overnight. The membranes were exposed to theKodak films; antiviral activity was calculated from the reduction in HBVDNA levels (EC₅₀). The EC₅₀ for antiviral activity was calculated fromthe dose response curves of active compounds. Assay performance overtime was monitored by the use of the standard positive control compoundsETV, BAY 41-4109, and HAP-1. Results are illustrated in Table 3.

Cytotoxity (CC₅₀) was measured in this same HepG2-2.2.15 cell line usinga CellTiter Blue-based cytotoxicity assay employed as recommended bymanufacturer (Promega). All compounds in Table 3 demonstrated lowtoxicity at 5 μM.

TABLE 3 “Activity” represents activity in dot-blot-assay (‘+’indicates >50% activity at 10 μM) Compound Activity Compound Activity 065 +  078 +  079 +  119 +  121 +  126 +  129 +  148 +  191 +  208 + 242 +  258 +  282 +  318 +  332 +  349 +  366 +  407 +  419 +  451 + 462 +  478 +  501 +  541 +  553 +  595 +  610D2 +  646 +  659D2 + 677R +  688 +  713D2 +  719D1 +  725D1 +  743D1 +  758 +  765 +  775 + 803 +  820D2 +  826 +  843 +  867D2 +  885 +  890 +  900 +  901 + 903 +  914 +  916 +  927 +  928 +  935 +  946D2 +  953 +  955D1 + 955D2 +  958 +  959 +  960D1 +  960D2 +  989D1 + 1042 + 1057 + 1087 +1094S + 1099 + 1106 + 1113 + 1114 + 1116 + 1129 + 1130 + 1134CT2 +1135D1 + 1149 + 1153 + 1157 + 1161 + 1189 + 1283 + 1338 + 1339 + 1345 +1374CT1 + 1374CT2 + 1378CT2 + 1379 + 1380 + 1404 + 1410 + 1413 + 1420 +824D2 +

Example Prevention of HBV Pre-Genomic RNA (pgRNA) Incorporation

The compounds of the invention were assessed for their ability tosuppress both extracellular and intracellular HBV DNA production in twodifferent cell culture models of HBV replication. A particle-gel assaythat allows quantitation of intracellular viral capsids, as well asencapsidated pre-genomic RNA and DNA, was performed. The assay relied onagarose gel separation of viral capsid from free capsid/core subunitsand viral pg-RNA and DNA.

This assay revealed that the compounds of the invention preventpackaging of pre-genomic RNA into the viral capsid without significanteffect on intracellular core particle levels. This effect is consistentwith the biochemical activity of the compounds of the invention, whichact as allosteric effectors that misdirect in vitro assembly leading toformation of aberrant, non-functional particles. The potent antiviraleffect is due to that pg-RNA encapsidation is required for viral DNAsynthesis.

The disclosures of each and every patent, patent application, andpublication cited herein are hereby incorporated herein by reference intheir entirety.

While the invention has been disclosed with reference to specificembodiments, it is apparent that other embodiments and variations ofthis invention may be devised by others skilled in the art withoutdeparting from the true spirit and scope of the invention. The appendedclaims are intended to be construed to include all such embodiments andequivalent variations.

What is claimed is:
 1. A compound of Formula IV:

or pharmaceutically acceptable salts thereof; wherein R⁴ is H whereineach R⁵ is independently selected at each occurrence from the groupconsisting of CH₃, C₁-C₆ alkoxy, halo, —CN, —NO₂, —C₁-C₆ haloalkyl,—C₁-C₆ dihaloalkyl and —C₁-C₆ trihaloalkyl; R¹⁰ is OH, C₁-C₆ alkyl, orhalo R¹¹ is a bond or C₁-C₃ alkylene, R² is independently selected ateach occurrence from the group consisting of halo and w is 1 or 2; eachoccurrence of x is independently selected from the group consisting of0, 1, and 2; each occurrence of y is independently selected from thegroup consisting of 1, 2, and 3; and each occurrence of z isindependently selected from the group consisting of 0, 1, 2, and
 3. 2.The compound of claim 1, wherein the compound of Formula IV is of theFormula IVa:

or pharmaceutically acceptable salts thereof.
 3. The compound of claim1, wherein each R⁵ is independently selected at each occurrence from thegroup consisting of CH₃, C₁-C₆ alkoxy, halo, fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, andtrichloromethyl; R¹⁰ is OH or C₁-C₆ alkyl; R¹¹ is a bond or C₁-C₃alkylene; R² is independently selected at each occurrence from the groupconsisting of halo and —C₁-C₆ alkyl.
 4. The compound of claim 1, whereinR⁵ is 3-F, 3-Cl, 3-CH₃, 3-CH₂F, 3-CHF₂, 4-F, 3-CH₃-4-F, 3-C1-4-F,3-Br-4-F, 3,4,5-trifluoro, 3,4,5-trichloro, or 3-chloro-4,5-difluoro. 5.The compound of claim 1, wherein R¹¹ is a bond or C₁-C₃ alkylene; R¹⁰ isOH, halo, or C₁-C₆ alkyl; and z is 0 or
 1. 6. A compound of Formula IVb:

and pharmaceutically acceptable salts thereof; wherein G¹ isindependently selected at each occurrence from CH₃, OCH₃, halo, CF₃,CCl₃, CH₂C1, CCl₂H, CF₂H, CH₂F, and CF₃; G² is H, C₁-C₄ alkyl, or halo;G³ is OH, CH₂OH, or CH₂CH₂OH; G⁴ is H, OH, halo, or C₁-C₆ alkyl; and yis 1, 2, or
 3. 7. The compound of claim 1, wherein the compound ofFormula IV is of the Formula IVc:

or pharmaceutically acceptable salts thereof; wherein X is halo; G¹ ishydrogen or halo; G² is H, C₁-C₄ alkyl, or halo; and G⁴ is H, halo,C₁-C₄ alkyl, or OH.
 8. The compound of claim 6, wherein G² is C₁-C₄alkyl or halo.
 9. A pharmaceutical composition comprising a compoundaccording to claim 1, or a salt, solvate or N-oxide thereof.
 10. Amethod of treating an HBV infection in an individual in need thereof,comprising administering to the individual a therapeutically effectiveamount of a compound according to claim
 1. 11. A method of reducing theviral load associated with an HBV infection in an individual in needthereof, comprising administering to the individual a therapeuticallyeffective amount of a compound according to claim
 1. 12. The method ofclaim 10, further comprising administering to the individual at leastone additional therapeutic agent selected from the group consisting of aHBV polymerase inhibitor, interferon, viral entry inhibitor, viralmaturation inhibitor, literature-described capsid assembly modulator,reverse transcriptase inhibitor, a TLR-agonist, and a combinationthereof.
 13. The method of claim 12, wherein the reverse transcriptaseinhibitor is at least one of Zidovudine, Didanosine, Zalcitabine,2′,3′-dideoxyadenosine, Stavudine, Lamivudine, Abacavir, Emtricitabine,Entecavir, Apricitabine, Atevirapine, ribavirin, acyclovir, famciclovir,valacyclovir, ganciclovir, valganciclovir, Tenofovir, Adefovir,cidofovir, Efavirenz, Nevirapine, Delavirdine, or Etravirine.
 14. Themethod of claim 12, wherein the TLR-agonist is selected from the groupconsisting of SM360320 (9-benzyl-8-hydroxy-2-(2-methoxy-ethoxy)adenine)and AZD 8848(methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(4-morpholinyl)propyl]amino}methyl)phenyl]acetate).15. The compound of claim 1, wherein w is
 1. 16. The compound of claim3, wherein w is
 1. 17. The compound of claim 1, wherein the compound ofFormula IV is selected from:

or a pharmaceutically acceptable salt thereof.
 18. The compound of claim1, wherein the compound of Formula IV is selected from:

or a pharmaceutically acceptable salt thereof.